Supplementary Appendix
`
`This appendix has been provided by the authors to give readers additional information about their work.
`
`Supplement to: Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing
`multiple sclerosis. N Engl J Med 2010;362:416-26. DOI: 10.1056/NEJMoa0902533.
`
`Merck 2027
`TWi v Merck
`IPR2023-00049
`
`

`

`APPENDIX: SUPPLEMENTAL INFORMATION
`
`METHODS
`ADDITIONAL STUDY DETAILS
`CLARITY – safety and efficacy of oral cladribine in subjects with relapsing-remitting
`multiple sclerosis, ClinicalTrials.gov identifier: NCT00213135, EudraCT number:
`2004-005148-28
`
`The study was conducted in accordance with the ethical principles of the Declaration
`of Helsinki and the International Conference on Harmonization Tripartite Guidelines
`for Good Clinical Practice.
`
`ASSESSMENT SCHEDULE
`Clinical laboratory tests, including chemistry, hematology and urinalysis, were
`performed by a central laboratory at pre-study evaluation and at Study Day 1 and
`Weeks 5, 9, 13, 16, 24, 36, 44, 48, 52, 60, 72, 84 and 96 (see Supplemental Figure
`1). Hematology analyses were also conducted at Weeks 2, 55, 66 and 78.
`
`Supplemental Figure 1. Study design and timing of assessments
`
`1
`
`

`

`Supplemental Figure 2. Patient Enrollment and Disposition.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Withdrawal data shown are study discontinuations.
`
`*Other reasons for discontinuation in the placebo and cladribine 3.5 and 5.25 mg/kg groups comprise
`consent withdrawal for administrative, convenience and personal reasons.
`
`Note: Two deaths occurred after patients withdrew from study, one in each cladribine group.
`
`PROTOCOL FOR THE MANAGEMENT OF HEMATOLOGICAL EVENTS
`For severe events (Grade 3) attributable to the study drug, treatment could be
`interrupted at the discretion of the investigator until resolution to a mild/moderate
`event (Grade 0 or 1). This could be repeated if the Grade 3 event reoccurred, but
`treatment discontinuation was required for a third recurrence of Grade 3 event, its
`persistence after a 4-week treatment interruption, or the occurrence of Grade 4
`toxicity. For hematological parameters, the threshold levels for discontinuation
`(Grade 4 toxicity values) were defined as hemoglobin levels of <4.0 mmol/L (65 g/L);
`leukocyte counts (total white blood cells) of <1 x109 /L; platelet counts of <25 x109 /L;
`and lymphocyte counts of <0.2 x109 /L.
`
`2
`
`

`

`RESULTS
`EFFECTS ON PERIPHERAL LYMPHOCYTES AND NEUTROPHILS
`Treatment with cladribine tablets resulted in a rapid reduction in median lymphocyte
`counts reaching nadir values at Week 9 (change from baseline –45.8%) for the
`cladribine tablets 3.5 mg/kg treatment group, and at Week 16 (change from baseline
`–64.0%) for the cladribine tablets 5.25 mg/kg treatment group, i.e. at 3–4 weeks after
`completion of the active treatment courses (Supplemental Figure 3). A gradual, only
`modest increase in median lymphocyte counts ensued and at Week 48, prior to
`initiation of re-treatment, median lymphocyte counts were –35.6% and –49.6% from
`baseline for the cladribine tablets 3.5 mg/kg and 5.25 mg/kg treatment groups,
`respectively. Re-treatment in the second 48-week treatment period with two
`additional cladribine tablets treatment courses resulted in an additional, but lesser
`magnitude reduction in median lymphocyte counts that reached nadir 3–8 weeks
`after last treatment (Week 60 for the 3.5 mg/kg group, and Week 55 for the 5.25
`mg/kg group) followed again by gradual return to levels seen prior to re-treatment.
`Reductions in median lymphocytes persisted to study end (–43.5% and –48.3% from
`baseline at Week 96, and –43.3% and –48.3% at last assessment for the cladribine
`tablets 3.5 mg/kg and 5.25 mg/kg treatment groups, respectively). The overall effect
`on reduction in median neutrophil counts was much less pronounced by comparison,
`with median neutrophil counts –15.4% and –18.0% from baseline at Week 96 and
`–15.4% and –17.5% at last assessment for the cladribine tablets 3.5 mg/kg and 5.25
`mg/kg treatment groups, respectively (Supplemental Figure 3).
`
`3
`
`

`

`Supplemental Figure 3. Median Cell Counts by Treatment Group Over Time for (A)
`Lymphocytes and (B) Neutrophils
`
`Estimates for the median used the Hodges-Lehmann estimator based on the Sign statistic.
`Error bars indicate the 5-95 percentile range for cell counts at each time point.
`Arrows indicate start of each short-course of treatment: black arrows indicate cladribine
`tablets courses; grey arrows indicate placebo course for the 3.5 mg/kg group and cladribine
`tablets for the 5.25 mg/kg group
`
`4
`
`

`

`SUMMARY OF MAXIMAL EFFECTS ON LYMPHOCYTE COUNTS
`ACCORDING TO CTCAE LABORATORY CRITERIA
`All patients experienced reductions in their lymphocyte count as expected based on
`the mechanism of action of cladribine. Lymphocyte counts therefore remained within
`normal limits (grade 0) for only 10.2% of patients in the 3.5 mg/kg group and 4.2% in
`the 5.25 mg/kg group during the 96 week study vs. 83.2% of patients in the placebo
`group (Supplemental Table 1). Grade 3 or 4 lymphopenia occurred in 25.6% of
`patients in the 3.5 mg/kg group and 45.0% in the 5.25 mg/kg group, vs. 0.5% in the
`placebo group. The majority of the grade 4 lymphopenia incidence resulted following
`re-dosing of patients already experiencing grade 3 lymphopenia (this was the
`situation for all 3 cases of grade 4 lymphopenia in the 3.5 mg/kg group and for 9/13
`cases in the 5.25 mg/kg group). The ongoing clinical development protocols have
`since been amended to avoid dosing subjects experiencing grade 3 lymphopenia.
`
`
`Supplemental Table 1. Summary of Maximum Laboratory CTCAE grades over the
`96-week Study.
`
`Grade, n (%)
`
`Haemoglobin
`
`
`
`
`
`
`
`
`
`
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Neutrophils
`
`
`
`
`
`
`
`
`
`
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Placebo
`
`(N=435)
`
`
`
`329 (75.6)
`
`88 (20.2)
`
`15 (3.4)
`
`3 (0.7)
`
`0
`
`
`
`365 (83.9)
`
`34 (7.8)
`
`18 (4.1)
`
`12 (2.8)
`
`6 (1.4)
`
`Cladribine
`
`3.5 mg/kg
`
`(N=430)
`
`
`
`296 (68.8)
`
`101 (23.5)
`
`27 (6.3)
`
`5 (1.2)
`
`0
`
`
`
`327 (76.0)
`
`52 (12.1)
`
`38 (8.8)
`
`5 (1.2)
`
`7 (1.6)
`
`Cladribine
`
` 5.25 mg/kg
`
`(N=454)
`
`
`
`326 (71.8)
`
`112 (24.7)
`
`15 (3.3)
`
`1 (0.2)
`
`0
`
`
`
`314 (69.2)
`
`81 (17.8)
`
`40 (8.8)
`
`14 (3.1)
`
`5 (1.1)
`
`5
`
`

`

`Lymphocytes
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Platelets
`
`0
`
`1
`
`2
`
`3
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`
`362 (83.2)
`
`51 (11.7)
`
`20 (4.6)
`
`2 (0.5)
`
`0
`
`
`
`415 (95.4)
`
`16 (3.7)
`
`3 (0.7)
`
`1 (0.2)
`
`0
`
`
`
`44 (10.2)
`
`113 (26.3)
`
`162 (37.7)
`
`107 (24.9)
`
`3 (0.7)
`
`
`
`383 (89.1)
`
`44 (10.2)
`
`1 (0.2)
`
`0
`
`0
`
`
`
`19 (4.2)
`
`52 (11.5)
`
`179 (39.4)
`
`191 (42.1)
`
`13 (2.9)
`
`
`
`412 (90.7)
`
`42 (9.3)
`
`0
`
`0
`
`0
`
`RELATIONSHIP BETWEEN LYMPHOCYTE COUNTS AND ZOSTER
`
`20 patients developed herpes zoster infections (including 1 case of herpes zoster
`oticus): 8 patients in the 3.5 mg/kg group and 12 in the 5.25 mg/kg group. In the 3.5
`mg/kg group, 5 out of the 8 patients (62.5%) experienced grade 3 or 4 lymphopenia
`at any time during the study, and 5 out of the 12 (41.7%) in the 5.25 mg/kg group did
`likewise. Herpes zoster infections therefore developed in 3.18% of cladribine tablet
`treated patients experiencing grade 3 or 4 lymphopenia at anytime during study
`compared with development in 1.75% of cladribine tablet treated patients that did not
`experience grade 3 or 4 lymphopenia during the study. Serial lymphocyte
`measurements reveal that in 70% of patients that developed zoster infection,
`lymphocyte counts were within grade 0, 1 or 2 at the approximate time of infection
`(lymphocyte counts were within grade 0, 1, 2 and 3 for 3, 3, 8 and 6 patients
`respectively).
`
`6
`
`

`

`Supplemental Table 2. Serious Treatment-Emergent Adverse Events Over the 96-week
`
`Study.
`
`Data shown as number (%) patients with each event
`
`
`
` System Organ Class
`
`
`
` Preferred Term
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`Any serious adverse event
`
`28 (6.4)
`
`36 (8.4)
`
`41 (9.0)
`
`77 (8.7)
`
`Infections and infestations
`
`7 (1.6)
`
`10 (2.3)
`
`13 (2.9)
`
`23 (2.6)
`
` Pneumonia
`
` Adnexitis
`
` Appendicitis
`
` Pyelonephritis
`
` Urinary tract infection
`
` Actinomycosis
`
` Chronic sinusitis
`
` Cystitis
`
`3 (0.7)
`
`3 (0.7)
`
`0
`
`2 (0.5)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`2 (0.5)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`3 (0.7)
`
`2 (0.4)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`6 (0.7)
`
`2 (0.2)
`
`0
`
`2 (0.2)
`
`2 (0.2)
`
`1 (0.1)
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
` Endometritis
`
` Hepatitis C
`
` Herpes zoster
`
` Herpes zoster infection neurological
`
` Herpes zoster oticus
`
`
`
`
`
`Influenza
`
`Lung abscess
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
` Myocarditis bacterial
`
`1 (0.2)
`
` Orchitis
`
` Respiratory tract infection
`
` Salpingo-oophoritis
`
` Subcutaneous abscess
`
`
`
`Tuberculosis
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.1)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 ( 0.2)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`7
`
`

`

`
`
` System Organ Class
`
`
`
` Preferred Term
`
`Hepatobiliary disorders
`
` Cholelithiasis
`
` Hepatitis toxic
`
` Cholecystitis
`
` Cholecystitis acute
`
` Hepatic cyst
`
` Hepatitis
`
` Hepatitis acute
`
` Hepatosplenomegaly
`
`
`
`Liver disorder
`
`Gastrointestinal disorders
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`3 (0.7)
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`2 (0.5)
`
`0
`
`3 (0.7)
`
`1 (0.2)
`
`1 (0.2)
`
`6 (1.3)
`
`2 (0.4)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`4 (0.9)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`5 (1.1)
`
`1 (0.2)
`
`9 (1.0)
`
`3 (0.3)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`9 (1.0)
`
`1 (0.1)
`
` Abdominal pain upper
`
` Colitis ulcerative
`
`
`
`Food poisoning
`
` Gastric ulcer
`
` Gastritis erosive
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
` Gastrointestinal motility disorder
`
`1 (0.2)
`
` Haemorrhoids
`
`
`
`
`
`Ileus
`
`Inguinal hernia
`
` Nausea
`
` Pancreatitis acute
`
` Pancreatitis relapsing
`
` Peritonitis
`
` Small intestinal perforation
`
`
`
`Toothache
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`8
`
`

`

`
`
` System Organ Class
`
`
`
` Preferred Term
`
` Vomiting
`
`Injury, poisoning and procedural
`
`complications
`
` Ankle fracture
`
` Fall
`
` Concussion
`
` Facial bones fracture
`
` Femoral neck fracture
`
` Femur fracture
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
`2 (0.5)
`
`9 (2.1)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2 ( 0.5)
`
`2 (0.5)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`9 (1.0)
`
`2 (0.2)
`
`2 (0.2)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
` Joint dislocation
`
` Lumbar vertebral fracture
`
` Overdose
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
` Pneumothorax traumatic
`
`1 (0.2)
`
`0
`
` Postoperative ileus
`
` Radius fracture
`
` Rib fracture
`
` Subdural haematoma
`
` Tibia fracture
`
` Upper limb fracture
`
` Wound dehiscence
`
`Neoplasms benign, malignant and
`
`unspecified (including cysts and polyps)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`6 (1.4)
`
`4 (0.9)
`
`10 (1.1)
`
`9
`
`

`

`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`
`
` System Organ Class
`
`
`
` Preferred Term
`
` Uterine leiomyoma
`
` Cervix carcinoma stage 0
`
` Malignant melanoma
`
` Myelodysplastic syndrome
`
` Ovarian cancer
`
` Pancreatic carcinoma metastatic
`
`Psychiatric disorders
`
` Suicide attempt
`
` Completed suicide
`
` Delirium
`
` Depression
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`4 (0.9)
`
`0
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`3 (0.7)
`
`0
`
`2 (0.4)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`3 (0.7)
`
`2 (0.4)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`5 (0.6)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`4 (0.5)
`
`2 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
`0
`
`0
`
`0
`
`0
`
`
`
`Intentional self-injury
`
`1 (0.2)
`
` Mental disorder
`
` Panic attack
`
` Schizophrenia, paranoid type
`
`Cardiac disorders
`
` Acute myocardial infarction
`
` Angina pectoris
`
` Arrhythmia
`
` Bundle branch block left
`
` Cardiac hypertrophy
`
` Cardio-respiratory arrest
`
` Cardiomyopathy
`
` Myocardial infarction
`
` Prinzmetal angina
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`4 (0.9)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`General disorders and administration
`
`2 (0.5)
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`2 (0.4)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`3 (0.3)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
`0
`
`0
`
`1 (0.2)
`
`4 (0.9)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`5 (0.6)
`
`10
`
`

`

`
`
` System Organ Class
`
`
`
` Preferred Term
`
`site conditions
`
` Chest pain
`
` Pyrexia
`
` Asthenia
`
` Drowning
`
` Non-cardiac chest pain
`
` Edema peripheral
`
`Musculoskeletal and connective tissue
`
`disorders
`
` Pain in extremity
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`6 (0.7)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`4 (0.9)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`2 (0.5)
`
`0
`
`0
`
` Arthritis
`
` Bone pain
`
`
`
`Intervertebral disc protrusion
`
` Myalgia
`
` Osteitis
`
`Respiratory, thoracic and mediastinal
`
`disorders
`
` Dyspnea
`
` Pulmonary embolism
`
` Asthma
`
` Lung infiltration
`
` Pulmonary edema
`
`Nervous system disorders
`
`0
`
`0
`
`0
`
`0
`
`0
`
`3 (0.7)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`2 (0.5)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`4 (0.9)
`
`2 (0.4)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`4 (0.5)
`
`2 (0.2)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`2 (0.5)
`
`2 (0.4)
`
`4 (0.5)
`
`11
`
`

`

`
`
` System Organ Class
`
`
`
` Preferred Term
`
` Altered state of consciousness
`
` Convulsion
`
` Epilepsy
`
` Facial spasm
`
` Haemorrhagic stroke
`
` Syncope
`
`Pregnancy, puerperium and perinatal
`
`conditions
`
` Abortion spontaneous
`
` Pregnancy
`
` Ectopic pregnancy
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`2 (0.5)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.1)
`
`2 (0.5)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`2 (0.4)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`4 (0.5)
`
`2 (0.2)
`
`2 (0.2)
`
`1 (0.1)
`
`3 (0.7)
`
`2 (0.4)
`
`5 (0.6)
`
`Blood and lymphatic system disorders
`
` Lymphopenia
`
` Neutropenia
`
` Leukopenia
`
` Pancytopenia
`
` Thrombocytopenia
`
`Renal and urinary disorders
`
` Calculus ureteric
`
` Nephrolithiasis
`
` Nephrosclerosis
`
` Renal artery stenosis
`
` Renal colic
`
` Renal failure chronic
`
`Reproductive system and breast
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`3 (0.7)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`2 (0.5)
`
`1 (0.2)
`
`2 (0.5)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`4 (0.5)
`
`2 (0.2)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`3 (0.3)
`
`0
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`disorders
`
`1 (0.2)
`
`1 (0.2)
`
`3 (0.7)
`
`4 (0.5)
`
`12
`
`

`

`
`
` System Organ Class
`
`
`
` Preferred Term
`
` Breast dysplasia
`
` Menorrhagia
`
` Metrorrhagia
`
` Ovarian cyst
`
` Uterine hemorrhage
`
`Skin and subcutaneous tissue disorders
`
` Hidradenitis
`
` Lichen sclerosus
`
` Purpura
`
` Rash generalized
`
` Skin reaction
`
`Cladribine
`
`Cladribine
`
`5.25
`
`Overall
`
`Placebo
`
`3.5 mg/kg
`
`mg/kg
`
`Cladribine
`
` (N=435)
`
`(N=430)
`
`(N=454)
`
`(N=884)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`3 (0.7)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`4 (0.5)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`2 (0.2)
`
`Vascular disorders
`
` Arterial disorder
`
` Deep vein thrombosis
`
` Hypertension
`
`Immune system disorders
`
` Hypersensitivity
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`Metabolism and nutrition disorders
`
`1 (0.2)
`
` Cachexia
`
` Hyperglycemia
`
` Hypoproteinemia
`
`Endocrine disorders
`
` Hyperthyroidism
`
`Eye disorders
`
` Eyelid ptosis
`
`
`
`0
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2 (0.4)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`2 (0.4)
`
`2 (0.4)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`1 (0.2)
`
`1 (0.2)
`
`1 (0.2)
`
`0
`
`0
`
`0
`
`1 0.1)
`
`1 (0.1)
`
`2 (0.2)
`
`2 (0.2)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`1 (0.1)
`
`1 (0.1)
`
`1 (0.1)
`
`0
`
`0
`
`13
`
`

`

`DEATHS
`There were six deaths in total; four patients died during the study and two following
`study withdrawal (total 2 deaths from each treatment group).
`
`During study: In the 3.5 mg/kg group, a 42-year-old, obese (120 kg) man with a
`history of type 2 diabetes died 8 months after his last treatment dose due to acute
`myocardial infarction. In the 5.25 mg/kg group, a 40-year-old man died of drowning
`after receiving 4 courses of treatment (4 months after his last treatment dose). Two
`deaths were reported in the placebo group: a 37-year-old female with a history of
`depression committed suicide 1 month after her last treatment and a 40-year-old
`female with a history of essential hypertension died of hemorrhagic stroke 8 months
`after her last treatment dose. All deaths during the study were considered by
`investigators as unlikely to be related to study medication.
`
`Following study withdrawal: In the 3.5 mg/kg group a 61-year-old woman died of
`pancreatic carcinoma with liver infiltration. The diagnosis of pancreatic carcinoma in
`this subject was considered unlikely to be related to treatment. In the 5.25 mg/kg
`group, a 21-year-old female developed pancytopenia and an apparent
`myelodysplastic syndrome with recurrent bilateral alveolar-interstitial lung infiltrates
`after receiving her first and only treatment cycle of cladribine tablets (0.875 mg/kg).
`Six months post-treatment, she died from an acute cardiopulmonary arrest
`considered to be due to severe exacerbation of latent tuberculosis. At post-mortem,
`the chronic pathological nature of lesions in the liver and lungs suggested that the
`tuberculosis was long-standing and likely present in latent form prior to cladribine
`treatment. Cladribine therapy likely contributed to the tuberculosis reactivation. What
`was reported as myelodysplasia was likely reactive bone marrow changes caused by
`her tuberculosis infection and was probably not true myelodysplasia.
`
`STUDY INVESTIGATORS AND OTHER PARTICIPANTS
`The following people participated in the CLARITY study: Study Steering Committee: Queen Mary
`University of London, Blizard Institute of Cell and Molecular Science, Barts and The London School of
`Medicine and Dentistry, Department of Neurology, Royal London Hospital, UK – G.Giovannoni
`(chairperson); Università Vita-Salute San Raffaele, Italy – G. Comi; University of Medicine and Dentistry
`New Jersey, NJ – S.Cook; The Ohio State University, OH, USA – K.Rammohan; Bamberg Hospital /
`University of Erlangen, Germany – P.Rieckmann; Danish MS Research Center, Rigshospitalitet,
`Copenhagen, Denmark – P.Soelberg Sørensen; CHU de Lille, University of Lille-Nord de France,
`France – P.Vermersch. Data and Safety Monitoring Board: M.Sandberg-Wollheim (chairperson,
`neurologist); Wolfson Institute of Preventive Medicine, Queen Mary University of London, UK – J.Cuzick
`
`14
`
`

`

`(biostatistician), Lund University Hospital, Sweden – G.Juliusson (hematologist); S.Reingold (multiple
`sclerosis expert). CLARITY Study Group Investigators: Australia: Royal Melbourne Hospital, Victoria
`– J.King; MS Clinical Trials Research Unit, Brain and Mind Research Institute, The University of Sydney,
`NSW – J.Pollard; St. Vincent’s Hospital, Melbourne, Victoria – L.Sedal. Austria: Landesnervenklinik
`Wagner-Jauregg, Linz – F.Aichner; Krankenhaus der Barmherzigen Brüder Neurologie, Linz –
`C.Eggers. Belgium: CHU Ourthe-Amblève, Service de Neurologie – D.Dive; Biomedisch
`Onderzoeksinstituut, Limburgs Universitair Centrum, Universiteit Hasselt, Deepenbeek – R.Medaer.
`Brazil: Hospital da Restauração, Ala Sul Recife – M.Ferreira. Bulgaria: UMHAT Stara Zagora EAD,
`Stara Zagora – I.Manchev; University Neurology Hospital "St. Naum", Sofia – I.Milanov; National Heart
`Hospital, Neurology Department, Special Hospital for Active, Treatment of Cardio-vascular Disease,
`Sofia – L.Haralanov; University Hospital "St. Marina", Varna – N.Deleva; MBAL Ruse AD, 2nd
`Department of Neurology, Ruse – N.Petrova; Medical University Pleven, I-st base Department of
`Neurology, Pleven – P.Bozhinov; University Hospital "St. Georgi", Department of Neurology, Plovdiv –
`Z.Zahariev; University Hospital Pleven, Pleven – B.Stamenov; University Hospital Alexandrovska, Sofia
`– P.Shotekov; MBAL Shoumen AD, Department of Neurology, Shumen – I.Petrov; Military Medical
`Academy, Sofia – R. Moskov. Canada: Centre Hospitalier Affilié Hôpital de l'Enfant-Jésus, Quebec –
`F.Émond; Ottawa Hospital, Ottawa – M. Freedman; Hôpital Charles Lemoyne, Quebec –
`F.Grand’Maison; CHVO - Hôpital de Hull, Multiple Sclerosis Clinic, Quebec – F.Jacques; Burnaby
`Hospital, Vancouver Fraser Health Multiple Sclerosis Clinic – G.Vorobeychik. Croatia: University
`Hospital Sestre Milosrdnice, Zagreb – V.Demarin; General Hospital Karlovac – M.Kovacicek; University
`Hospital Split – I.Lusic; General Hospital Dr Ivo Pedisic, Split – T.Perhat-Bucevic. Czech Republic: MS
`Center, Department of Neurology, Fakultni poliklinika, Prague – E.Havrdova; Neurological Department
`of Faculty Hospital, Hradec Králové – R.Talab; Faculty Hospital, Neurological Department, Olomouc –
`P.Kanovsky. Denmark: Danish MS Research Center, Rigshospitalitet, Copenhagen – P.Soelberg
`Sørensen; Aarhus sygehus, Scleroseklinikken, Arhus – T.Petersen. Estonia: West-Tallinn Central
`Hospital, MS Centre, Tallinn – K.Gross-Paju; Tartu University Hospital, Tartu – I.Kalbe; East Tallin
`Central Hospital, Talinn – T.Toomsoo. Finland: University of Tampere – I.Elovaara; Suomen
`Terveystalo Clinical Research, Turku (cid:237) J-P. Eralinna; Oulu University Hospital, Clinic of Neurology –
`M.Reunanen. France: Hôpital Gabriel Montpied, Clermont-Ferrand – P.Clavelou; Centre Hospitalier
`Universitaire de Nantes, Saint Herblain – P.Damier; CHU de Nancy – Universite' de Nancy, France –
`M.Debouverie; Hôpital Pontchaillou, Rennes, France – G.Edan; Fondation a de Rothschild, Paris –
`O.Gout; CHU Nimes – P.Labauge; Centre Hospitalier Universitaire de Nantes – D.Laplaud,
`S.Wiertlewski; CHU de Lille, University of Lille-Nord de France – P.Vermersch. Germany:
`Diakoniekrankenhaus Henriettenstiftung, Department of Neurology, Hannover – F.Heidenreich;
`Caritaskrankenhaus Bad Mergentheim – M.Mäurer; Heinrich-Heine-University, Duesseldorf –
`B.Kieseier; University Hospital Essen – V.Limmroth; Justus-Liebig-Universitat Giessen – P.Oschmann;
`St. Joseph Hospital der Ruhr Universität Bochum, Klinik für Neurologie (cid:237) S.Schimrigk; Klinik und
`Poliklinik für Neurologie, Universitätsklinikum der Universität Regensbur (cid:237) A.Steinbrecher; University of
`Rostock – U.Zettl; Klinik für Neurologie, Goethe Universität, Frankfurt am Main – U.Ziemann. Greece:
`General Hospital of Athens "G. Gennimatas" – K.Karageorgiou; University Hospital of Ioannina –
`A.Kyritsis; Henry Dunant Hospital, Athens – A. Papadimitriou. Italy: Dip.Scienze Neurologiche e
`Psichiatriche, Clinica Neurologica I, Univ. degli Studi di Firenze – M.P. Amato; Clinica Neurologica,
`Università Tor Vergata, Rome – G.Bernardi; Dipartimento Scienze Neurologiche, Nuovo Policlinico
`Federico II, Napoli – V.B.Morra; Università Vita-Salute San Raffaele – G. Comi; Day Hospital
`Neurologia, Ospedale San Camillo – S. Galgani; Multiple Sclerosis Centre – Veneto Region,
`
`15
`
`

`

`Department of Neuroscience, University Hospital of Padova – P.Gallo; Centro Sclerosi Multipla, Catania
`– F.Patti; Centro Sclerosi Multipla, Cagliari – M.Marrosu; S.Andrea Multiple Sclerosis Center, “La
`Sapienza” University, Rome – C.Pozzilli; Department of Neurological and Psychiatric Sciences,
`University of Bari – M.Trojano; DINOG – Dipartimento di Neuroscienze, Oftalmologia e Genetica,
`Università degli Studi di Genova – G.L.Mancardi. Lebanon: The Lebanese Hospital, Beirut – S.Gebeily;
`Hôpital Hotel-Dieu De France, Beirut – S.Koussa; Sahel General Hospital, Beirut – M.Wehbe; American
`University of Beirut – B.Yamout. Lithuania: Kaunas Medical University Hospital – A.Vaitkus. Latvia:
`Vecmilgravis Hospital, Riga – M.Metra. Morocco: CHU Hassan II, Department of Neurology, Fes –
`O.Messouak; Service de Neurologie, Hôpital Militaire MOHAMED V, Rabat – R.Mossaddaq; CHU Ibn
`Rochd, Casablanca – I.Slassi; Hopital des specialites Rabat – M.Yahyaoui. The Netherlands:
`Academic MS Center Sittard, Sittard-Geleen – R.M.M. Hupperts. Poland: 2nd Department of Neurology,
`Institute of Psychiatry and Neurology, Warsaw – A.Czlonkowska; Neurology Clinic, Medical Academy in
`Pozna, Poznan – W. Kozubski; Neurology Clinic, Medical Academy in Gdansk – W.Nyka; Department
`of Neurology, Medical University of Lodz – K.Selmaj; Jagiellonian University Medical College, Krakow –
`A.Szczudlik. Portugal: Hospital de S.Marcos, Serviço de Neurologia, Bragal – J.Figueiredo; Hospital
`dos Capuchos, Serviço de Neurologia, Lisbon – R.Pedrosa. Russia: Siberian State Medical University,
`Tomsk – V.Alifirova; Rostov State Medical University, Rostov-on-Don – V.Balyazin; Kemerovo State
`Medical Academy, Kemerovo – O.Barbarash; Municipal Medical Unit, “City Hospital #33”, Nizhny
`Novgorod – A.Belova; Russian State Medical University & Moscow MS Centre, Moscow – A.Boyko,
`E.Gusev; Clinical Hospital #122 of Medical Biological Federal Agency Russian Federation,
`St.Petersburg – A.Elchaninov; Kazan State Medical University, Kazan – E.Jacoupov; Medical Academy
`of Postgraduate Education, Clinic and Chair of Neurology, St. Petersburg – N.Julev; Moscow Regional
`Scientific Research, Clinical Institute named after M. F. Vladimirsky, Moscow – S.Kotov; Vladimir
`Regional Clinical Hospital, Institution of Public Health, Vladimir – A.Kudryavtsev; Kursk Regional Clinical
`Hospital, Kursk – V.Laskov; Sverdlovsk RegionalClinical Hospital, Ekaterinburg – O.Lesnyak; Military
`Medical Academy named after S.M.Kirov of Department of Defense of Russian Federation, Clinic of
`Neurology, St.Petersburg – M.Odinak; Kaluga Regional Hospital, Kaluga – E.Pasechnik; Samara State
`Medical University – I.Poverennonva; St.Petersburg State Medical, University named after I.P.Pavlov,
`University – A.Skoromets; Yaroslavl State Medical Academy Department of Diseases of Nervous
`System, Yaroslavl – N.Spirin; Institute of Human Brain of Russian Academy of Science, St.Petersburg –
`I.Stolyarov; Rehabilitalogical department of neurological disorders of Central Clinical Hospital #2, n.a.
`Semashko of OAO RZD, Moscow (cid:237) O.Vorobieva; Saratov State Medical University, Saratov –
`O.Voskresenskaya; St.Petersburg Region Clinical Hospital – L. Zaslavskiy; State Institution Science
`Research Institute of Clinical and Experimental Lymphology, Novosibirsk (cid:237) E.Zonova. Saudi Arabia:
`King Faisal Specialist Hospital and Research Centre – S.Bohlega; King Abdullah International Medical
`Research Centre & King Saud Bin Abdulaziz University for Health Sciences, Riyadh – M.El-Jumah.
`Serbia and Montenegro: Institute of Neurology Clinical Center of Serbia, Belgrade – J.Drulovic; Clinic
`of Neurology, Clinical Centre Vojvodina, Novi Sad – C.Nadj. Switzerland: University Hospital Zurich –
`N.Goebels; Centre Hospitalier Universitaire Vaudois, Lausanne – M.Schluep; Tunisia: Hôpital
`Fattouma Bourghiba Monastir – M.Ayed-Frih; Institut National de Neurologie, Tunis – F.Hentati; Hôpital
`Bourguiba, Sfax – C.Mhiri; Hôpital Charles Nicolle – A. Mrabet; Hôpital Militaire de Tunis – R.Mrissa.
`Turkey: 9 Eylül University Medical School, Izmir – E.Idiman; Hacettepe University Tip Fakultesi, Ankara
`– R. Karabudak; Uludag University Medical School, Bursa – O.F.Turan. UK: Department of Neurology,
`Hull Royal Infirmary, Hull – Fayyaz Ahmed; Queen's Medical Centre, Division of Clinical Neurology,
`University of Nottingham – C.Constantinescu; Queen Mary University of London, Blizard Institute of Cell
`
`16
`
`

`

`and Molecular Science, Barts and The London School of Medicine and Dentistry, Department of
`Neurology, Royal London Hospital – G.Giovannoni; Keele University, University Hospital of North
`Staffordshire, Stoke-on-Trent – C.Hawkins; Multiple Sclerosis Group, Department of Neurology, John
`Radcliffe Hospital, Oxford – J.Palace; Royal Hallamshire Hospital, Sheffield – B.Sharrack. Ukraine:
`Institute for Clinical Radiology, Research Centre for Radiation Medicine, Academy of Medical Sciences
`of Ukraine, Kyiv – K.Loganovsky; Vinnytsya Regional Psychoneurological Hospital, Department of
`Neurology, Vinnytsia National Medical University, Vinnytsya – S.Moskovko; Lviv Regional Central
`Hospital, Department of Neurology, Lviv State Medical University, Lviv, Ukraine – T.Nehrych; Institute
`of Neurology, Psychiatry and Narcology of the AMS Ukraine, Kharkiv – N.P.Voloshyna. USA: Medford
`Neurological & Spine Clinic, Medford, OR – W.Carlini; University of Medicine and Dentistry New Jersey,
`NJ – S.Cook; MS Center of Atlanta, Atlanta, GA – J.English; Alpine Clinical Research Center, Boulder,
`CO – G.Garmany; [No affiliation], USA – S.Glyman; Neurology & Neurosurgery Associates of Tacoma
`PLLC, Tacoma, WA – J.Huddlestone; Duke University Medical Center, NC – B.Hurwitz; Capitol
`Neurology, Charlestown, WV – K.Kresa-Reahl; [Merck Serono] – D.Mikol; MS Center of Oklahoma,
`Merci Neuroscience Institute, OK – G.Pardo; The Ohio State University, OH – K.Rammohan; Neurology
`Consultants of the Carolinas, NC – H.Rao; Minor & James Medical, PLLC, Seattle, WA – M.Reif;
`Shepherd Center, Inc, Atlanta, GA – B.Thrower; Maryland Center for MS Neurology, Baltimore, MD –
`W.Royal; Neurological Associates of Tulsa, Inc., Tulsa, OK – R.Webb; Consultants in Neurology Ltd,
`Northbrook, IL – D.Wynn, C.Naga, N.Allen, K.Lin; Rush University Medical Center, Chicago, IL –
`D.Stefoski, R.Balabanov.
`
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`17
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