PREMIERE: Prospective Observational Long-term Safety Registry of Multiple Sclerosis Participants Who Have Participated in Cladribine Clinical Trials

• Sponsor: EMD Serono (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01013350
• Collaborator: (none)
• Enrollment: 1,161
• Location: 1
• Actual Duration (Months): 106.8
• Patients Per Site Per Month: 10.9

Study Details

Study Description

Brief Summary

Prospective Observational Long-term Safety Registry of Multiple Sclerosis Participants who Have Participated in Cladribine Clinical Trials

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis

Study Design

• Study Type: Observational
• Actual Enrollment: 1161 participants
• Observational Model: Other
• Time Perspective: Prospective
• Official Title: Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies (PREMIERE)
• Actual Study Start Date: Nov 30, 2009
• Actual Primary Completion Date: Oct 25, 2018
• Actual Study Completion Date: Oct 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Never Exposed to Cladribine All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826 , NCT00641537, NCT00938366 and NCT00725985).
Exposed to Cladribine All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537, NCT00938366 and NCT00725985).

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Serious Adverse Drug Reactions (SADRs) [up to 3251 days]

   SADR is an adverse drug reaction that fulfils at least one of the seriousness criterion; results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is otherwise considered as medically important. An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the restoration, correction, or modification or physiological functions. Number of participants with SADRs were reported.

2. Time to Resolution of Lymphopenia, Among Registry Participants With Persistent Lymphopenia [up to 3251 days]

   Persistent lymphopenia was defined as Grade 3 (less than [<] 500-200 per millimeter [mm] ^3 or < 0.5-0.2 multiply [*]10^9 per Liter) or Grade 4 (< 200/mm^3 or < 0.2*10^9 per Liter) lymphopenia as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The resolution is the achievement of a CTCAE Grade 1 (< lower limit of normal [LLN] to 800 per mm^3 or < LLN to 0.8*10^9 per Liter) or Grade 0 (< 910 per mm^3 ) lymphocyte count. Persistent Lymphopenia was reported only in Cladribine group, hence results are reported only for "Exposed to Cladribine" arm. Time to resolution is reported.

3. Number of Participants With Adverse Events (AEs) in the "Blood and Lymphatic System Disorders" System Organ Class (SOC) and in the "Neoplasms Benign, Malignant, and Unspecified" SOC [up to 3251 days]

   An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.

Secondary Outcome Measures

1. Number of Participants With Pregnancy Outcomes [up to 3251 days]

   Pregnancies occurred among female participants exposed to cladribine were identified by a participant-reported positive pregnancy test and at least a 2-week delay in menses, or a participant-reported pregnancy diagnosed by a physician. Pregnancy outcomes were Live birth, Induced abortion (Termination), Spontaneous loss (Miscarriage) (< 22 weeks), Foetal death (stillbirth) (>=22 weeks), Ectopic pregnancy, Congenital malformations and others (unknown). Number of participants as per pregnancy outcome category were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Prior enrollment into selected oral cladribine clinical trials as of randomization to either study drug or placebo, once participation in the clinical trial has ended

• Written informed consent was given

Exclusion Criteria:

• Participants who cannot be reached by telephone

• Participants unable to answer the registry questionnaires and who do not have a next of kin or caregiver able to answer the registry questionnaires

• Participants who - either during the lag interval or subsequently enter an interventional study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Outcome Sciences, Inc	Cambridge	Massachusetts	United States	02139

Sponsors and Collaborators

• EMD Serono

Investigators

• Study Director: Medical Responsible, EMD Serono Inc., an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

• Study Protocol - Jul 20, 2016
• Statistical Analysis Plan - Nov 21, 2018

More Information

Publications

None provided.

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT01013350
• Other Study ID Numbers: EMR700568-012; 2009-017978-21
• First Posted: Nov 13, 2009
• Last Update Posted: Nov 15, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by EMD Serono: Multiple Sclerosis; Cladribine; PREMIERE; Observational study
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis

Study Results

Participant Flow

Pre-assignment Detail	Study enrolled participants from previous clinical trials (NCT00213135, NCT00436826, NCT00641537, NCT00938366 and NCT00725985) and were exposed either to placebo matched to cladribine or cladribine itself. 13 enrolled participants from NCT00938366 were excluded from safety analysis as the dose was relatively lower compared with other studies.

Arm/Group Title	Never Exposed to Cladribine	Exposed to Cladribine
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826 , NCT00641537, NCT00938366 and NCT00725985).	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537, NCT00938366 and NCT00725985).
Period Title: Overall Study
STARTED	198	963
Safety Analysis Set	198	950
COMPLETED	160	771
NOT COMPLETED	38	192

Baseline Characteristics

Arm/Group Title	Never Exposed to Cladribine	Exposed to Cladribine	Total
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).	Total of all reporting groups
Overall Participants	198	950	1148
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.4 (10.2)	40.6 (10.8)	40.1 (10.8)
Sex: Female, Male (Count of Participants)
Female	141 71.2%	632 66.5%	773 67.3%
Male	57 28.8%	318 33.5%	375 32.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	0 0%	1 0.1%
Asian	5 2.5%	13 1.4%	18 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	7 0.7%	7 0.6%
White	190 96%	925 97.4%	1115 97.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1%	5 0.5%	7 0.6%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious Adverse Drug Reactions (SADRs)
Description	SADR is an adverse drug reaction that fulfils at least one of the seriousness criterion; results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is otherwise considered as medically important. An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the restoration, correction, or modification or physiological functions. Number of participants with SADRs were reported.
Time Frame	up to 3251 days

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants in the current study who either received placebo matched to cladribine or cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826 , NCT00641537 and NCT00725985).

Arm/Group Title	Never Exposed to Cladribine	Exposed to Cladribine
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
Measure Participants	198	950
Count of Participants [Participants]	1 0.5%	14 1.5%

2. Primary Outcome

Title	Time to Resolution of Lymphopenia, Among Registry Participants With Persistent Lymphopenia
Description	Persistent lymphopenia was defined as Grade 3 (less than [<] 500-200 per millimeter [mm] ^3 or < 0.5-0.2 multiply [*]10^9 per Liter) or Grade 4 (< 200/mm^3 or < 0.2*10^9 per Liter) lymphopenia as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The resolution is the achievement of a CTCAE Grade 1 (< lower limit of normal [LLN] to 800 per mm^3 or < LLN to 0.8*10^9 per Liter) or Grade 0 (< 910 per mm^3 ) lymphocyte count. Persistent Lymphopenia was reported only in Cladribine group, hence results are reported only for "Exposed to Cladribine" arm. Time to resolution is reported.
Time Frame	up to 3251 days

Outcome Measure Data

Analysis Population Description

Lymphocyte Population included participants from safety analysis set who had persistent lymphopenia. Here, "overall number of participants analyzed" signified participants with resolved lymphopenia.

Arm/Group Title	Exposed to Cladribine
Arm/Group Description	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
Measure Participants	41
Mean (Standard Deviation) [months]	30.22 (17.78)

3. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) in the "Blood and Lymphatic System Disorders" System Organ Class (SOC) and in the "Neoplasms Benign, Malignant, and Unspecified" SOC
Description	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.
Time Frame	up to 3251 days

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants in the current study who either received placebo matched to cladribine or cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826 , NCT00641537, NCT00725985).

Arm/Group Title	Never Exposed to Cladribine	Exposed to Cladribine
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
Measure Participants	198	950
Blood and Lymphatic System Disorders SOC	18 9.1%	92 9.7%
Neoplasms Benign, Malignant, and Unspecified SOC	4 2%	25 2.6%

4. Secondary Outcome

Title	Number of Participants With Pregnancy Outcomes
Description	Pregnancies occurred among female participants exposed to cladribine were identified by a participant-reported positive pregnancy test and at least a 2-week delay in menses, or a participant-reported pregnancy diagnosed by a physician. Pregnancy outcomes were Live birth, Induced abortion (Termination), Spontaneous loss (Miscarriage) (< 22 weeks), Foetal death (stillbirth) (>=22 weeks), Ectopic pregnancy, Congenital malformations and others (unknown). Number of participants as per pregnancy outcome category were reported.
Time Frame	up to 3251 days

Outcome Measure Data

Analysis Population Description

Safety analysis set. Here, "Overall Number of Participants Analyzed" signifies number of participants with pregnancies.

Arm/Group Title	Never Exposed to Cladribine	Exposed to Cladribine
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).	All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
Measure Participants	34	57
Live Birth	23 11.6%	39 4.1%
Induced Abortion (Termination)	3 1.5%	3 0.3%
Spontaneous Loss (Miscarriage)	2 1%	3 0.3%
Foetal Death (Still birth)	0 0%	1 0.1%
Ectopic Pregnancy	0 0%	1 0.1%
Congenital Malformations	0 0%	0 0%
Unknown	6 3%	10 1.1%

Adverse Events

Time Frame	up to 3251 days
Adverse Event Reporting Description	Safety analysis set included all participants in the current study who either received placebo matched to cladribine or cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
Arm/Group Title	Never Exposed to Cladribine		Exposed to Cladribine
Arm/Group Description	All participants who received placebo matched to cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).		All participants who received cladribine in previously conducted clinical trials (NCT Number: NCT00213135, NCT00436826, NCT00641537 and NCT00725985).
All Cause Mortality
	Never Exposed to Cladribine		Exposed to Cladribine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/198 (1.5%)		5/950 (0.5%)
Serious Adverse Events
	Never Exposed to Cladribine		Exposed to Cladribine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/198 (5.1%)		63/950 (6.6%)
Blood and lymphatic system disorders
Immune thrombocytopenic purpura	0/198 (0%)		1/950 (0.1%)
Leukocytosis	0/198 (0%)		1/950 (0.1%)
Thrombocytopenic purpura	0/198 (0%)		1/950 (0.1%)
Cardiac disorders
Cardiac failure	1/198 (0.5%)		0/950 (0%)
Coronary artery insufficiency	1/198 (0.5%)		0/950 (0%)
Myocardial infarction	0/198 (0%)		1/950 (0.1%)
Congenital, familial and genetic disorders
Dandy-Walker syndrome	1/198 (0.5%)		0/950 (0%)
Ear and labyrinth disorders
Vertigo	0/198 (0%)		1/950 (0.1%)
Vertigo positional	0/198 (0%)		1/950 (0.1%)
Endocrine disorders
Goitre	0/198 (0%)		1/950 (0.1%)
Thyroid mass	0/198 (0%)		1/950 (0.1%)
Eye disorders
Vision blurred	1/198 (0.5%)		0/950 (0%)
Gastrointestinal disorders
Dysphagia	0/198 (0%)		1/950 (0.1%)
Gastrointestinal melanosis	0/198 (0%)		1/950 (0.1%)
Pancreatitis acute	0/198 (0%)		1/950 (0.1%)
General disorders
Accidental death	0/198 (0%)		1/950 (0.1%)
Non-cardiac chest pain	0/198 (0%)		1/950 (0.1%)
Pyrexia	0/198 (0%)		1/950 (0.1%)
Hepatobiliary disorders
Cholecystitis	0/198 (0%)		1/950 (0.1%)
Cholecystitis acute	0/198 (0%)		1/950 (0.1%)
Infections and infestations
Anal abscess	0/198 (0%)		1/950 (0.1%)
Appendicitis	0/198 (0%)		1/950 (0.1%)
Bronchitis	1/198 (0.5%)		0/950 (0%)
Clostridium difficile colitis	0/198 (0%)		1/950 (0.1%)
Diverticulitis	0/198 (0%)		1/950 (0.1%)
Meningoencephalitis herpetic	0/198 (0%)		1/950 (0.1%)
Pneumonia	0/198 (0%)		2/950 (0.2%)
Pneumonia bacterial	0/198 (0%)		1/950 (0.1%)
Pneumonia viral	0/198 (0%)		1/950 (0.1%)
Pulmonary tuberculosis	0/198 (0%)		1/950 (0.1%)
Tooth infection	0/198 (0%)		1/950 (0.1%)
Urinary tract infection	1/198 (0.5%)		0/950 (0%)
Injury, poisoning and procedural complications
Brain herniation	0/198 (0%)		1/950 (0.1%)
Femur fracture	0/198 (0%)		1/950 (0.1%)
Hip fracture	0/198 (0%)		1/950 (0.1%)
Lumbar vertebral fracture	0/198 (0%)		1/950 (0.1%)
Subdural haemorrhage	0/198 (0%)		1/950 (0.1%)
Metabolism and nutrition disorders
Hypokalaemia	0/198 (0%)		1/950 (0.1%)
Hyponatraemia	0/198 (0%)		1/950 (0.1%)
Musculoskeletal and connective tissue disorders
Back pain	0/198 (0%)		2/950 (0.2%)
Intervertebral disc degeneration	0/198 (0%)		1/950 (0.1%)
Intervertebral disc protrusion	0/198 (0%)		1/950 (0.1%)
Spondylolisthesis	0/198 (0%)		1/950 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/198 (0%)		1/950 (0.1%)
Breast cancer	0/198 (0%)		1/950 (0.1%)
Breast cancer stage II	0/198 (0%)		1/950 (0.1%)
Cervix carcinoma	0/198 (0%)		1/950 (0.1%)
Cervix carcinoma stage 0	1/198 (0.5%)		0/950 (0%)
Colon cancer stage 0	0/198 (0%)		1/950 (0.1%)
Metastases to lung	0/198 (0%)		2/950 (0.2%)
Nonkeratinising carcinoma of nasopharynx	0/198 (0%)		1/950 (0.1%)
Ovarian germ cell teratoma benign	0/198 (0%)		1/950 (0.1%)
Papillary thyroid cancer	0/198 (0%)		1/950 (0.1%)
Polycythaemia vera	0/198 (0%)		1/950 (0.1%)
Rectal adenocarcinoma	0/198 (0%)		1/950 (0.1%)
Rectal adenoma	0/198 (0%)		1/950 (0.1%)
Rectal cancer	0/198 (0%)		1/950 (0.1%)
Thyroid adenoma	0/198 (0%)		1/950 (0.1%)
Uterine leiomyoma	0/198 (0%)		1/950 (0.1%)
Nervous system disorders
Ataxia	0/198 (0%)		1/950 (0.1%)
Brain oedema	0/198 (0%)		1/950 (0.1%)
Cerebellar syndrome	0/198 (0%)		1/950 (0.1%)
Cerebral infarction	0/198 (0%)		1/950 (0.1%)
Dizziness	0/198 (0%)		1/950 (0.1%)
Hemiparaesthesia	1/198 (0.5%)		0/950 (0%)
Loss of consciousness	0/198 (0%)		1/950 (0.1%)
Monoparesis	0/198 (0%)		1/950 (0.1%)
Multiple sclerosis	1/198 (0.5%)		1/950 (0.1%)
Multiple sclerosis relapse	0/198 (0%)		8/950 (0.8%)
Optic neuritis	1/198 (0.5%)		1/950 (0.1%)
Relapsing-remitting multiple sclerosis	0/198 (0%)		1/950 (0.1%)
Pregnancy, puerperium and perinatal conditions
Abortion	1/198 (0.5%)		0/950 (0%)
Abortion missed	0/198 (0%)		1/950 (0.1%)
Abortion spontaneous	0/198 (0%)		2/950 (0.2%)
Abortion threatened	0/198 (0%)		1/950 (0.1%)
Foetal death	0/198 (0%)		2/950 (0.2%)
Foetal distress syndrome	0/198 (0%)		1/950 (0.1%)
Premature separation of placenta	1/198 (0.5%)		0/950 (0%)
Psychiatric disorders
Depression	0/198 (0%)		1/950 (0.1%)
Jealous delusion	0/198 (0%)		1/950 (0.1%)
Suicide attempt	0/198 (0%)		1/950 (0.1%)
Renal and urinary disorders
Acute kidney injury	0/198 (0%)		1/950 (0.1%)
Urinary incontinence	0/198 (0%)		1/950 (0.1%)
Urinary retention	0/198 (0%)		1/950 (0.1%)
Respiratory, thoracic and mediastinal disorders
Neonatal anoxia	0/198 (0%)		1/950 (0.1%)
Pneumothorax	0/198 (0%)		1/950 (0.1%)
Surgical and medical procedures
Abortion induced	1/198 (0.5%)		0/950 (0%)
Stem cell transplant	0/198 (0%)		1/950 (0.1%)
Vascular disorders
Thrombophlebitis	0/198 (0%)		1/950 (0.1%)
Other (Not Including Serious) Adverse Events
	Never Exposed to Cladribine		Exposed to Cladribine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/198 (13.1%)		124/950 (13.1%)
Blood and lymphatic system disorders
Lymphopenia	15/198 (7.6%)		76/950 (8%)
Nervous system disorders
Multiple sclerosis relapse	11/198 (5.6%)		48/950 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.