Clinical trial NCT00641537: CLARITY Extension Study
Official title: A Phase IIIb, Double-Blind, Placebo-Controlled, Multicenter, Parallel Group, Extension Trial to Evaluate the Safety and Tolerability of Oral Cladribine in Subjects With Relapsing-Remitting Multiple Sclerosis Who Have Completed Trial 25643 (CLARITY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Relapsing-Remitting Multiple Sclerosis
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2008-03-24
Enrollment: 867
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this extension trial was to further evaluate the safety and tolerability of oral cladribine in subjects who have previously completed treatment within Trial 25643 (CLARITY). This trial also explored clinical benefit of prolonged 192-week versus 96-week treatment.


Eligibility criteria: Inclusion Criteria:

* Randomized in Trial 25643 and satisfied one of the following:

  * Completed randomized treatment course and scheduled visits for the full 96 weeks; or
  * Did not complete the randomized treatment course in Trial 25643 but elected to receive rescue treatment with Rebif®, another beta-interferon, or glatiramer acetate and completed scheduled clinic visits for the full 96 weeks; or
  * Did not complete the randomized treatment course in Trial 25643, declined rescue with Rebif®, another beta-interferon, or glatiramer acetate and still completed scheduled clinic visits for the full 96 weeks; or
  * Did not complete the randomized treatment course in Trial 25643, were not eligible for rescue option with Rebif®, and still completed scheduled clinic visits for the full 96 weeks
* Male or female, between 18 and 65 years of age (inclusive, at time of informed consent for Trial 25643)
* No medical history or evidence of latent tuberculosis infection (LTBI) or tuberculosis (TB), as evidenced by TB skin test or chest X-ray
* All of the following laboratory hematologic parameters evaluated as normal (as define below, inclusively) within 28 days of first dosing of blinded study medication at study Day 1:

  * Hemoglobin = 11.6 to 16.2 gram per deciliter (g/dL)
  * Leukocytes (total white blood cell) = 4.1 to 12.3\*10\^3 per microliter
  * Absolute lymphocyte count (ALC) = 1.02 to 3.36\*10\^3 per microliter
  * Absolute neutrophil count (ANC) = 2.03 to 8.36\*10\^3 per microliter
  * Platelet count = 140 to 450\*10\^3 per microliter
* Other protocol-defined inclusion/exclusion criteria may apply

Exclusion Criteria:

* Participants who were not enrolled in Trial 25643
* Participant has moderate to severe renal impairment
* Use of mitoxantrone, total lymphoid irradiation, myelosuppressive therapy, campath-1h, cyclophosphamide, azathioprine, methotrexate or natalizumab at any time during and since Trial 25643
* Use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIG) or plasmapheresis at any time during and since Trial 25643
* Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days before Study Day 1

Primary outcomes:
measure: Safety Population: Percentage of Participants With at Least 1 Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE) Grade 4 Hematologic and Hepatic Toxicity
timeFrame: Baseline up to Week 120
measure: Safety Population: Mean Change From Baseline in Absolute Lymphocyte Count, Platelet, Neutrophils and Leukocytes at Week 120
timeFrame: Baseline, Week 120
measure: Safety Population: Mean Change From Baseline in Hemoglobin at Week 120
timeFrame: Baseline, Week 120
measure: Safety Population: Mean Change From Baseline in Aspartate Aminotransferase and Alanine Aminotransferase at Week 120
timeFrame: Baseline, Week 120
measure: Safety Population: Mean Change From Baseline in Bilirubin at Week 120
timeFrame: Baseline, Week 120
measure: Safety Population: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline up to Week 120
measure: SAFUP Analysis Set: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: Baseline up to Week 120
measure: Safety Population: Number of Participants Who Developed Infections (Herpes Viral Infection, Viral Infectious Disorder and Opportunistic Infection), Infection-related Adverse Events and Malignancies
timeFrame: Baseline up to Week 120
measure: SAFUP Analysis Set: Number of Participants Who Developed Infections (Herpes Viral Infection, Viral Infectious Disorder and Opportunistic Infection), Infection-related Adverse Events and Malignancies
timeFrame: Baseline up to Week 120
measure: Safety Population: Time to First Grade 3 or 4 Hematological Toxicity and Liver Toxicity
timeFrame: Baseline up to Week 120
measure: Safety Population: Median Time to Recovery From Grade 3 or 4 Hematological and Hepatic Toxicity
timeFrame: Baseline up to Week 120
measure: Safety Population: Mean Time to Recovery From Grade 3 or 4 Hematological and Liver Toxicity
timeFrame: Baseline up to Week 120
measure: Safety Population: Median Time to Nadir of Absolute Lymphocyte Count
timeFrame: Baseline up to Week 120
measure: Safety Population: Mean Time to Nadir of Absolute Lymphocyte Count
timeFrame: Baseline up to Week 120
measure: Safety Population: Mean Time to Recovery From Nadir of Absolute Lymphocyte Count to Normal Value
timeFrame: Baseline up to Week 120
measure: Safety Population: Mean Change in Corrected QT (QTc) Interval From Baseline
timeFrame: Baseline, Week 5, 48, 52 and 96
Secondary outcomes:
Other outcomes:
Locations:
city: Boulder
country: United States
facility: Research Site
state: Colorado
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Northbrook
country: United States
facility: Research Site
state: Illinois
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Henderson
country: United States
facility: Research Site
state: Nevada
city: Newark
country: United States
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state: New Jersey
city: Charlotte
country: United States
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state: North Carolina
city: Durham
country: United States
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state: North Carolina
city: Columbus
country: United States
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state: Ohio
city: Oklahoma City
country: United States
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state: Oklahoma
city: Tulsa
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state: Oklahoma
city: Medford
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state: Oregon
city: Seattle
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state: Washington
city: Tacoma
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state: Washington
city: Charleston
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state: West Virginia
city: Camperdown
country: Australia
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city: Melbourne
country: Australia
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city: Victoria
country: Australia
facility: Research Site
city: Linz
country: Austria
facility: Research Site
city: Diepenbeek
country: Belgium
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city: Esneux
country: Belgium
facility: Research Site
city: Recife
country: Brazil
facility: Research Site
city: Pleven
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Shuman
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Zagora
country: Bulgaria
facility: Research Site
city: Burnaby
country: Canada
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city: Greenfield Park
country: Canada
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city: Ottawa
country: Canada
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city: Quebec
country: Canada
facility: Research Site
city: Karlovac
country: Croatia
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city: Sisak
country: Croatia
facility: Research Site
city: Split
country: Croatia
facility: Research Site
city: Hradec Králové
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Copenhagen
country: Denmark
facility: Research Site
city: Tallinn
country: Estonia
facility: Research Site
city: Tartu
country: Estonia
facility: Research Site
city: Oulu
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Clermont-Ferrand
country: France
facility: Research Site
city: Lille
country: France
facility: Research Site
city: Nancy
country: France
facility: Research Site
city: Nimes
country: France
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city: Paris
country: France
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city: Rennes
country: France
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city: Saint Herblain
country: France
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city: Bochum
country: Germany
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city: Frankfurt
country: Germany
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city: Giessen
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Regensburg
country: Germany
facility: Research Site
city: Rostock
country: Germany
facility: Research Site
city: Athens
country: Greece
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Cagliari
country: Italy
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
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city: Padova
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Beirut
country: Lebanon
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city: Beyrouth
country: Lebanon
facility: Research Site
city: Kaunas
country: Lithuania
facility: Research Site
city: Casablanca
country: Morocco
facility: Research Site
city: Fes
country: Morocco
facility: Research Site
city: Rabat
country: Morocco
facility: Research Site
city: Sittard- Geleen
country: Netherlands
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lodz
country: Poland
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city: Poznan
country: Poland
facility: Research Site
city: Warszawy
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Ekaterinburg
country: Russian Federation
facility: Research Site
city: Kaluga
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Kemerovo
country: Russian Federation
facility: Research Site
city: Kursk
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Nizhny Novgorod
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Rostov-on-Don
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Saratov
country: Russian Federation
facility: Reseach Site
city: St-Petersburg
country: Russian Federation
facility: Research Site
city: Tomsk
country: Russian Federation
facility: Research Site
city: Vladimir
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Riyadh
country: Saudi Arabia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: St. Gallen
country: Switzerland
facility: Research Site
city: Monastir
country: Tunisia
facility: Research Site
city: Sfax
country: Tunisia
facility: Research Site
city: Tunis
country: Tunisia
facility: Research Site
city: Bursa
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Kharkov
country: Ukraine
facility: Research Site
city: Kiev
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Vinnitsa
country: Ukraine
facility: Research Site
city: Hull
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Stoke-on-Trent
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References:
citation: Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist TP, Coyle PK, Dangond F, Alexandri N, Galazka A. Relapses in people with multiple sclerosis treated with cladribine tablets followed for up to 5 years: a plain language summary. Neurodegener Dis Manag. 2022 Dec;12(6):303-310. doi: 10.2217/nmt-2022-0019. Epub 2022 Aug 26.
citation: Giovannoni G, Comi G, Rammohan K, Rieckmann P, Dangond F, Jack D, Vermersch P. Disease stability over five years in people with multiple sclerosis treated with cladribine tablets: a plain language summary. Neurodegener Dis Manag. 2022 Dec;12(6):295-301. doi: 10.2217/nmt-2022-0018. Epub 2022 Aug 26.
citation: Giovannoni G, Coyle PK, Vermersch P, Walker B, Aldridge J, Nolting A, Galazka A, Lemieux C, Leist TP. Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets. Front Immunol. 2021 Dec 24;12:763433. doi: 10.3389/fimmu.2021.763433. eCollection 2021.
citation: Giovannoni G, Comi G, Rammohan K, Rieckmann P, Dangond F, Keller B, Jack D, Vermersch P. Long-Term Disease Stability Assessed by the Expanded Disability Status Scale in Patients Treated with Cladribine Tablets 3.5 mg/kg for Relapsing Multiple Sclerosis: An Exploratory Post Hoc Analysis of the CLARITY and CLARITY Extension Studies. Adv Ther. 2021 Sep;38(9):4975-4985. doi: 10.1007/s12325-021-01865-w. Epub 2021 Aug 9.
citation: De Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist T, Coyle PK, Dangond F, Keller B, Alexandri N, Galazka A. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: The CLARITY and CLARITY Extension studies. Mult Scler. 2022 Jan;28(1):111-120. doi: 10.1177/13524585211010294. Epub 2021 May 10.
citation: Giovannoni G, Galazka A, Schick R, Leist T, Comi G, Montalban X, Damian D, Dangond F, Cook S. Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety. Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
citation: Comi G, Cook S, Rammohan K, Soelberg Sorensen P, Vermersch P, Adeniji AK, Dangond F, Giovannoni G. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension study. Ther Adv Neurol Disord. 2018 Jan 23;11:1756285617753365. doi: 10.1177/1756285617753365. eCollection 2018.