Clinical Trial of Idebenone in Primary Progressive Multiple Sclerosis (IPPoMS)
Study Details
Study Description
Brief Summary
Background:
-
Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system that progressively weakens and destroys the pathways of the nervous system. About 10 percent to 15 percent of patients develop primary-progressive MS (PP-MS), characterized by progressive accumulation of disability from the disease onset, without any marked improvements or relapses. There are currently no effective treatments for PP-MS.
-
Idebenone is a manmade drug that is similar to a naturally occurring compound known as coenzyme Q10, a common dietary supplement. Research data suggest that idebenone may be able to limit demyelination and death of brain cells and thereby slow or halt the progression of neurological dysfunction such as that occurring in MS.
Objectives:
- To evaluate the safety and effectiveness of using idebenone to treat primary progressive MS.
Eligibility:
- Individuals between 18 and 65 years of age who have been diagnosed with primary progressive multiple sclerosis.
Design:
-
The study will last 3 years and will be divided into two parts: a 1-year pretreatment baseline and 2 years of treatment with either idebenone or a placebo.
-
Pre-treatment study: approximately 5 clinic visits over 1 year.
-
Visit 1: Comprehensive medical history and neurological examination, with brain scans and neurological tests.
-
Visit 2: Magnetic resonance imaging (MRI) scan of the spine and lymphocytapheresis (withdrawal of white blood cells for testing).
-
Visit 3: Lumbar puncture.
-
Visit 4: Skin biopsy.
-
Visit 5: Repeat MRI of the brain and spinal cord, as well as neurological tests; these tests will be scheduled over 2 days.
-
After the five pretreatment visits, patients will receive a 6-month supply of study medication (either idebenone or a placebo) to take three times a day with food
-
Patients will continue to have regular followup clinic visits with brain MRI scans, blood tests, and other evaluations of brain and nervous system function. Randomly selected participants will have additional MRI scans for further safety precautions.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Objective: The goal of this study is to assess the safety, therapeutic efficacy and mechanism of action of idebenone in primary-progressive multiple sclerosis (PP-MS) patients.
Study Population: Adult, untreated patients with PP-MS with disability ranging from none to moderately severe will be included in the trial. The upper age limit in this study has been set at 65; setting an age limit should permit us to focus on the potential neuroprotective effect of idebenone in PP-MS and limit the confounding factor of the natural aging process and its known negative influence on neuro-regeneration. Published data indicate that higher doses (10-50 mg/kg) of idebenone per day are required for beneficial effects on neurological disability in comparison to the lower doses (5-10mg/kg) that are sufficient for beneficial effects on cardiac/systemic functions in Friedreich s ataxia (FRDA) patients. Therefore, in order to target the CNS compartment, we will use a daily dose of 2250mg (750mg 3 times per day), which will provide target values of 10-50mg/kg for virtually all adult patients.
Design: This is a Phase I/II safety/efficacy trial with an adaptive trial design: one year of pretreatment baseline period serves the dual purpose of collecting patient-specific biomarkers of disease progression and collecting longitudinal neuroimaging and clinical data for selection of primary outcome measures. This baseline period is then followed by a double-blind, idebenone versus placebo treatment phase for a total of 2 years. Based on preliminary sample size estimates, current enrollment calls for a total of 66 patients (33 per arm).
Outcome Measures: Quantitative neuroimaging measures of central nervous system (CNS: i.e. brain and spinal cord) tissue destruction and clinical and functional (i.e. electrophysiological) measures of neurological disability will be collected every 6-12 months. Additionally, biomarkers focusing on analysis of reactive oxygen species (ROS) and oxidative stress will be collected every 12 months. The trial is currently powered using progression of brain atrophy as detected by SIENA methodology as the primary outcome measure. However, this may not be the most sensitive outcome available. In recognition of this, the trial has an adaptive design: i.e. it incorporates analysis of progression of CNS tissue destruction as measured by quantitative MRI markers and clinical/paraclinical markers defined as secondary outcome measures in the first 30 enrolled patients during the one year pre-treatment baseline, before randomization. All defined outcome measures collected in the first 30 enrolled patients will be transformed into z-scores and compared for the robustness of longitudinal change over the coefficient of variation. This will permit to select the most sensitive and most accurate outcome measure for detecting progression of CNS tissue damage. As a result, the primary outcome measure of this trial will be the comparison of individualized rates of brain atrophy progression between the idebenone and placebo groups after 2 years of treatment, unless the predetermined analysis of the pre-treatment baseline period in the first 30 enrolled subjects determines that one of the predefined secondary outcome measures has a higher z-score than brain atrophy measurement. In this case, the primary outcome would be the efficacy of idebenone versus placebo in inhibiting patient-specific slopes of functional or structural deterioration as measured by this more sensitive biomarker of CNS tissue destruction, yet to be defined by the analysis of the 1-year longitudinal data from pre-treatment baseline.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Idebenone Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. |
Drug: Idebenone
idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)
Other Names:
|
| Placebo Comparator: Placebo Placebo tablets administered orally as five tablets, three times per day with food. |
Other: placebo
lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in the Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) From Baseline to Treatment Phase [1-year pre-treatment baseline vs 2-year treatment period]
The AUCs of the CombiWISE scores during the 2-year treatment period was analyzed using an Analysis of Covariance (ANCOVA) model with the AUC of the pre-treatment CombiWISE scores, Baseline (Month 0) CombiWISE score and Baseline age as covariates. CombiWISE is a composite scale derived from Expanded Disability Status Scale (EDSS) , Scripps Neurological Disability Scale (SNRS), times 25 foot walk (25FW), and non-dominant hand of 9 hole peg test (9HPT) with a minimum value of 0 (no disability) and maximum value of 100 (maximum disability). The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18, and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases.
Secondary Outcome Measures
- Change in the AUC of Individualized Rates of Enlargement of Ventricular Volume From Baseline to Treatment Phase [1-year pre-treatment baseline vs 2-year treatment period]
The AUCs of the Ventricular volume scores (individualized rates of enlargement of segmented volume of lateral and 3rd ventricles) during the baseline and the 2-year treatment period were assessed using an ANCOVA model with the AUC of the pre-treatment Volumetric score, Baseline (Month 0) Volumetric score, and group as covariates. The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18 and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases.
- Disability Progression Measured by EDSS-plus [2-year treatment period]
Categorical time-to-event endpoints (EDSS-plus) were analyzed using Cox Proportional hazards models, with treatment group as a covariate. The EDSS-plus event was defined as disability progression on at least 1 of 3 components [EDSS, 25FW, and/or non-dominant hand 9HPT]) confirmed 6 months apart and with a ≥ 20% minimum threshold change for 25FW and non-dominant hand 9HPT). The patients who did not have an event during the study were censored at the time of the last assessment of EDSS-plus. The number of months from the date of first dose to date of event or censoring were used as endpoint. The measure is time to disease progression and unit of this measure is months.
- Change in Slopes of 25FW Time From Baseline to Treatment Phase [1-year pre-treatment baseline vs 2-year treatment period]
Lower extremity disability was measured by an average of two trials of timed 25 foot walk assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. The maximum time assigned for a trial is 180s. Patients unable to complete the 25 foot trial within this time limit are coded as "179.9"
- Change in Slopes of 9HPT Time From Baseline to Treatment Phase [1-year pre-treatment baseline vs 2-year treatment period]
Upper extremity/fine motor movements disability was measured as an average of left and right hand time, with each hand assessed as an average of two trials with upper limit of 5 (300s) per trial. Patients unable to complete the task within this time are coded as "777" The outcome was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.
- Change in Slopes of SNRS From Baseline to Treatment Phase on [1-year pre-treatment baseline vs 2-year treatment period]
SNRS scale combines various elements of a neurological exam into a single number. The scale ranges from 100 to 0, where 100 marks no disability and 0 marks maximum disability. SNRS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.
- Change in Slopes of EDSS From Baseline to Treatment Phase [1-year pre-treatment baseline vs 2-year treatment period]
EDSS scale combines various elements of neurological exam. EDSS is a discrete scale ranging from 0 to 10 with 0.5 point increments. EDSS of 0 means no neurological disability, while EDSS of 10 marks death due to MS. EDSS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase.The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0.
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
-
PP-MS as determined by the 2005 modification of McDonald s diagnostic criteria
-
Age from 18-65 years (inclusive)
-
Expanded Disability Status Scale (EDSS) measure of neurological disability from 1 (no disability, clinical signs only) to 7 (ambulatory with bilateral support)
-
Able to provide informed consent
-
Willing to participate in all aspects of trial design and follow-up
-
If able to become pregnant or to father a child, agreeing to commit to the use of a reliable/accepted method of birth control (i.e. hormonal contraception (birth control pills, injected hormones, vaginal ring), intrauterine device, barrier methods with spermicide (diaphragm with spermicide, condom with spermicide) or surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner)) for the duration of treatment arm of the study
-
Not receiving any immunomodulatory/immunosuppressive therapies for a period of at least 3 months before enrollment in the study
-
No exposure to idebenone, coenzyme-Q(10) or other dietary supplements (such as antioxidants, mitochondrial-function promoting supplements or vitamins in excess of 3 times recommended daily doses) for a period of at least 1 month before enrollment in the study
EXCLUSION CRITERIA:
-
Alternative diagnoses that can explain neurological disability and MRI findings
-
Clinically significant medical disorders that, in the judgment of the investigators, could cause CNS tissue damage or limit its repair, or might expose the patient to undue risk of harm or prevent the patient from completing the study
-
History of hypersensitivity reaction to idebenone or coenzyme-Q (10)
-
Pregnant or lactating women. All women of child-bearing potential must have a negative pregnancy test prior to the medication phase of the study.
-
Abnormal screening/baseline blood tests exceeding any of the limits defined below:
- Serum alanine transaminase or aspartate transaminase levels greater than 3 times the upper limit of normal values
-
Total white blood cell count < 3,000/mm(3)
-
Platelet count < 85,000/mm(3)
-
Serum creatinine level > 2.0 mg/dl or eGFR (estimated glomerular filtration rate) <30
-
Positive pregnancy test
- Patients who are receiving any immunosuppressive therapies (including cytostatic agents) due to the concern that these drugs may contribute to neurodegeneration or limit CNS repair
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Bibiana Bielekova, M.D., National Institute of Allergy and Infectious Diseases (NIAID)
Study Documents (Full-Text)
More Information
Publications
- Artuch R, Aracil A, Mas A, Colomé C, Rissech M, Monrós E, Pineda M. Friedreich's ataxia: idebenone treatment in early stage patients. Neuropediatrics. 2002 Aug;33(4):190-3.
- Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, McFarland H, Henkart PA, Martin R. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5941-6. Epub 2006 Apr 3.
- Bieniek M, Altmann DR, Davies GR, Ingle GT, Rashid W, Sastre-Garriga J, Thompson AJ, Miller DH. Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Sep;77(9):1036-9. Epub 2006 Jun 22.
- 090197
- 09-I-0197
Study Results
Participant Flow
| Recruitment Details | Between November 1, 2009 and July 23, 2015, 85 patients were assessed for eligibility and enrolled into the IPPoMS trial at National Institutes of Health, Bethesda, MD |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Untreated | Idebenone | Placebo |
|---|---|---|---|
| Arm/Group Description | Patients in their first year baseline prior to study drug phase | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Period Title: Year 1: Baseline | |||
| STARTED | 85 | 0 | 0 |
| COMPLETED | 77 | 0 | 0 |
| NOT COMPLETED | 8 | 0 | 0 |
| Period Title: Year 1: Baseline | |||
| STARTED | 0 | 39 | 38 |
| COMPLETED | 0 | 33 | 33 |
| NOT COMPLETED | 0 | 6 | 5 |
Baseline Characteristics
| Arm/Group Title | Idebenone | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Total of all reporting groups |
| Overall Participants | 39 | 38 | 77 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
39
100%
|
37
97.4%
|
76
98.7%
|
| >=65 years |
0
0%
|
1
2.6%
|
1
1.3%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
17
43.6%
|
20
52.6%
|
37
48.1%
|
| Male |
22
56.4%
|
18
47.4%
|
40
51.9%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
1
2.6%
|
1
1.3%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
3
7.7%
|
3
7.9%
|
6
7.8%
|
| White |
36
92.3%
|
34
89.5%
|
70
90.9%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Age at Disease onset (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
43.2
|
42.6
|
42.9
|
| Time since disease onset at baseline (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
13.6
|
11.9
|
12.7
|
| Body Mass Index (kg/m2) [Mean (Full Range) ] | |||
| Mean (Full Range) [kg/m2] |
25.7
|
25.8
|
25.8
|
| History of Mononucleosis (Count of Participants) | |||
| Positive |
8
20.5%
|
6
15.8%
|
14
18.2%
|
| Negative |
19
48.7%
|
19
50%
|
38
49.4%
|
| Unknown |
12
30.8%
|
13
34.2%
|
25
32.5%
|
| Northern European Ancestry (Count of Participants) | |||
| Positive |
17
43.6%
|
18
47.4%
|
35
45.5%
|
| Negative |
5
12.8%
|
5
13.2%
|
10
13%
|
| Unknown |
17
43.6%
|
15
39.5%
|
32
41.6%
|
| Family History of MS (Count of Participants) | |||
| Positive |
13
33.3%
|
8
21.1%
|
21
27.3%
|
| Negative |
26
66.7%
|
28
73.7%
|
54
70.1%
|
| Unknown |
0
0%
|
2
5.3%
|
2
2.6%
|
| History of Smoking (Count of Participants) | |||
| Positive |
29
74.4%
|
30
78.9%
|
59
76.6%
|
| Negative |
9
23.1%
|
3
7.9%
|
12
15.6%
|
| Unknown |
1
2.6%
|
5
13.2%
|
6
7.8%
|
Outcome Measures
| Title | Change in the Area Under the Curve (AUC) of the Combinatorial Weight-Adjusted Disability Score (CombiWISE) From Baseline to Treatment Phase |
|---|---|
| Description | The AUCs of the CombiWISE scores during the 2-year treatment period was analyzed using an Analysis of Covariance (ANCOVA) model with the AUC of the pre-treatment CombiWISE scores, Baseline (Month 0) CombiWISE score and Baseline age as covariates. CombiWISE is a composite scale derived from Expanded Disability Status Scale (EDSS) , Scripps Neurological Disability Scale (SNRS), times 25 foot walk (25FW), and non-dominant hand of 9 hole peg test (9HPT) with a minimum value of 0 (no disability) and maximum value of 100 (maximum disability). The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18, and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases. |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary outcome was assessed in Intention-to-treat population of patients: all randomized patients who have at least one post-baseline (post Mo 0) efficacy assessment. 38 out of 39 patients randomized to idebenone and 35 out of 38 patients randomized to placebo fulfill this definition. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 38 | 35 |
| Mean (Standard Deviation) [units on a scale per year] |
-0.13
(2.17)
|
-1.04
(2.87)
|
| Title | Change in the AUC of Individualized Rates of Enlargement of Ventricular Volume From Baseline to Treatment Phase |
|---|---|
| Description | The AUCs of the Ventricular volume scores (individualized rates of enlargement of segmented volume of lateral and 3rd ventricles) during the baseline and the 2-year treatment period were assessed using an ANCOVA model with the AUC of the pre-treatment Volumetric score, Baseline (Month 0) Volumetric score, and group as covariates. The AUC values were calculated for both the pre-treatment baseline phase (from Months -12, -6, and 0) and for the double-blind phase (from Months 0, 6, 12, 18 and 24). Because the follow-up times varied from patient to patient, the AUC values were made comparable by scaling them by dividing the AUC value by the square of the actual duration (in years) of each of the phases. |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The primary outcome was assessed in Intention-to-treat population. Due to technical error in MRI images processing 2 out of 38 idebenone patients were excluded from the analysis. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 36 | 35 |
| Mean (Standard Deviation) [ml per year] |
-244
(1094.9)
|
35.4382
(1091.1)
|
| Title | Disability Progression Measured by EDSS-plus |
|---|---|
| Description | Categorical time-to-event endpoints (EDSS-plus) were analyzed using Cox Proportional hazards models, with treatment group as a covariate. The EDSS-plus event was defined as disability progression on at least 1 of 3 components [EDSS, 25FW, and/or non-dominant hand 9HPT]) confirmed 6 months apart and with a ≥ 20% minimum threshold change for 25FW and non-dominant hand 9HPT). The patients who did not have an event during the study were censored at the time of the last assessment of EDSS-plus. The number of months from the date of first dose to date of event or censoring were used as endpoint. The measure is time to disease progression and unit of this measure is months. |
| Time Frame | 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The outcome was assessed in the Intention-to-treat population of patients: all randomized patients who have at least one post-baseline (post Mo 0) efficacy assessment. 38 out of 39 patients randomized to idebenone and 35 out of 38 patients randomized to placebo fulfill this definition. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 38 | 35 |
| Median (95% Confidence Interval) [months] |
23.1
|
23.7
|
| Title | Change in Slopes of 25FW Time From Baseline to Treatment Phase |
|---|---|
| Description | Lower extremity disability was measured by an average of two trials of timed 25 foot walk assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. The maximum time assigned for a trial is 180s. Patients unable to complete the 25 foot trial within this time limit are coded as "179.9" |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The piecewise mixed-effect model only considers patient that completed all follow-up visits, therefore the Completer population (33 patients in placebo and 33 patients in the idebenone group) was considered for this analysis. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 33 | 33 |
| Mean (Standard Error) [seconds per year] |
0.02451
(0.01668)
|
-0.01015
(0.01889)
|
| Title | Change in Slopes of 9HPT Time From Baseline to Treatment Phase |
|---|---|
| Description | Upper extremity/fine motor movements disability was measured as an average of left and right hand time, with each hand assessed as an average of two trials with upper limit of 5 (300s) per trial. Patients unable to complete the task within this time are coded as "777" The outcome was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The piecewise mixed-effect model only considers patient that completed all follow-up visits, therefore the Completer population (33 patients in placebo and 33 patients in the idebenone group) was considered for this analysis. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 33 | 33 |
| Mean (Standard Error) [seconds per year] |
0.001693
(0.000843)
|
-0.0003
(0.000955)
|
| Title | Change in Slopes of SNRS From Baseline to Treatment Phase on |
|---|---|
| Description | SNRS scale combines various elements of a neurological exam into a single number. The scale ranges from 100 to 0, where 100 marks no disability and 0 marks maximum disability. SNRS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase. The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The piecewise mixed-effect model only considers patient that completed all follow-up visits, therefore the Completer population (33 patients in placebo and 33 patients in the idebenone group) was considered for this analysis. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 33 | 33 |
| Mean (Standard Error) [units on a scale per year] |
1.5728
(0.9743)
|
0.2315
(0.9702)
|
| Title | Change in Slopes of EDSS From Baseline to Treatment Phase |
|---|---|
| Description | EDSS scale combines various elements of neurological exam. EDSS is a discrete scale ranging from 0 to 10 with 0.5 point increments. EDSS of 0 means no neurological disability, while EDSS of 10 marks death due to MS. EDSS was assessed at month -12, -6, and 0 for the baseline phase and at month 0, 6, 12, 18, and 24 for the treatment phase.The progression rate was calculated as a difference between baseline and treatment slopes using a piecewise linear mixed-effect model with breaking point at month 0. |
| Time Frame | 1-year pre-treatment baseline vs 2-year treatment period |
Outcome Measure Data
| Analysis Population Description |
|---|
| The piecewise mixed-effect model only considers patient that completed all follow-up visits, therefore the Completer population (33 patients in placebo and 33 patients in the idebenone group) was considered for this analysis. |
| Arm/Group Title | Idebenone | Placebo |
|---|---|---|
| Arm/Group Description | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) |
| Measure Participants | 33 | 33 |
| Mean (Standard Error) [units on a scale per year] |
1.6148
(3.762)
|
-3.7879
(3.7214)
|
Adverse Events
| Time Frame | 3 years | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | First 1 year (Month -12 to Month 0), all patients were untreated - adverse events are reported on all 85 enrolled patients during this pre-treatment phase Next 2 years (Month 0 to Month 24) patients were randomized to placebo (38 patients) or idebenone (39 patients) - adverse events are collected on these 77 patients during the 2 year double-blind phase | |||||
| Arm/Group Title | Untreated | Idebenone | Placebo | |||
| Arm/Group Description | Patients in their first year baseline prior to study drug phase | Idebenone (150mg tablets) administered orally as five tablets, three times per day with food. Idebenone: idebenone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium povidone, magnesium stearate, silicon dioxide, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | Placebo tablets administered orally as five tablets, three times per day with food. placebo: lactose monohydrate, microcrystalline cellulose, magnesium stearate, film-coat: Opadry II 85F23495 (consisting of: aluminium lake, FD&C yellow #6, macrogol/PEG 3550, polyvinylalcohol, titanium dioxide, talc) | |||
All Cause Mortality |
||||||
| Untreated | Idebenone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/85 (0%) | 0/39 (0%) | 2/38 (5.3%) | |||
Serious Adverse Events |
||||||
| Untreated | Idebenone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 12/85 (14.1%) | 11/39 (28.2%) | 10/38 (26.3%) | |||
| Blood and lymphatic system disorders | ||||||
| Lymphadenopathy | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Eye disorders | ||||||
| Diplopia | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Constipation | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Cholecystectomy | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Peritoneal haemorrhage | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Intestinal obstruction | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 2/38 (5.3%) | 2 |
| Faecaloma | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| General disorders | ||||||
| Chest pain | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Asthenia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Condition aggravated | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Pain | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Peripheral swelling | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Pyrexia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Vascular stent occlusion | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Cholelithiasis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Cholecystitis acute | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Immune system disorders | ||||||
| Sarcoidosis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Infections and infestations | ||||||
| Urinary tract infection | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 2/38 (5.3%) | 2 |
| Lyme disease | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Pneumonia | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 2/38 (5.3%) | 2 |
| Influenza | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Localised infection | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Wound infection | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Escherichia urinary tract infecti | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Herpes zoster | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Sepsis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Fall | 3/85 (3.5%) | 3 | 2/39 (5.1%) | 2 | 2/38 (5.3%) | 2 |
| Laceration | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Ankle fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Fibula fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Post lumbar puncture syndrome | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Skin abrasion | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Upper limb fracture | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Joint injury | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Ligament rupture | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Tibia fracture | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Road traffic accident | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Alcohol poisoning | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Investigations | ||||||
| H1N1 influenza | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Pain in extremity | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Muscular weakness | 0/85 (0%) | 0 | 2/39 (5.1%) | 2 | 0/38 (0%) | 0 |
| Muscle rigidity | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Muscle spasticity | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Spinal osteoarthritis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Arthralgia | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Rheumatoid arthritis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Rotator cuff syndrome | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Prostate cancer | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Nervous system disorders | ||||||
| Dizziness | 0/85 (0%) | 0 | 2/39 (5.1%) | 2 | 0/38 (0%) | 0 |
| Trigeminal neuralgia | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Loss of consciousness | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Cervical cord compression | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Serotonin syndrome | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Cerebrovascular accident | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Diabetic hyperglycaemic coma | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Optic neuritis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Transient ischaemic attack | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Neurological symptom | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Psychiatric disorders | ||||||
| Stress | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Mental status changes | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Dysuria | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Reproductive system and breast disorders | ||||||
| Erectile dysfunction | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Dyspnoea | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Surgical and medical procedures | ||||||
| Catheter management | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Coronary arterial stent insertion | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Intrathecal pump insertion | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Prostatectomy | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Spinal cord operation | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Umbilical hernia repair (AE) | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Antibiotic therapy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Colostomy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Occupational therapy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Physical therapy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Surgery | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Vascular disorders | ||||||
| Deep vein thrombosis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Peripheral artery aneurysm | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Untreated | Idebenone | Placebo | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 28/85 (32.9%) | 15/39 (38.5%) | 11/38 (28.9%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 5/85 (5.9%) | 5 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Lymphopenia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Cardiac disorders | ||||||
| Tachycardia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Ear and labyrinth disorders | ||||||
| Middle ear effusion | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 2 |
| Hypoacusis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Vertigo | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Endocrine disorders | ||||||
| Goitre | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Eye disorders | ||||||
| Retinal detachment | 0/85 (0%) | 0 | 2/39 (5.1%) | 2 | 0/38 (0%) | 0 |
| Cataract | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Eye movement disorder | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Glaucoma | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 2/38 (5.3%) | 3 |
| Diarrhoea | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 2/38 (5.3%) | 2 |
| Vomiting | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 2/38 (5.3%) | 2 |
| Cholecystectomy | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Dental caries | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Dry mouth | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Melaena | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| General disorders | ||||||
| Oedema peripheral | 1/85 (1.2%) | 1 | 3/39 (7.7%) | 4 | 1/38 (2.6%) | 1 |
| Chest pain | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Asthenia | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 2/38 (5.3%) | 2 |
| Condition aggravated | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Gravitational oedema | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Pain | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| General symptom | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Peripheral swelling | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Systemic inflammatory response sy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Pyrexia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Hepatic lesion | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Infections and infestations | ||||||
| Urinary tract infection | 5/85 (5.9%) | 8 | 2/39 (5.1%) | 3 | 2/38 (5.3%) | 2 |
| Upper respiratory tract infection | 1/85 (1.2%) | 1 | 2/39 (5.1%) | 2 | 0/38 (0%) | 0 |
| Lyme disease | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Cellulitis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Post procedural infection | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Bacteriuria | 1/85 (1.2%) | 3 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Acute sinusitis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Pneumonia | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Influenza | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Body tinea | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Localised infection | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Wound infection | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Gastritis viral | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Genital herpes | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Oral infection | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Sinusitis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Tinea versicolor | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Staphylococcal infection | 1/85 (1.2%) | 3 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Onychomycosis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Fall | 4/85 (4.7%) | 4 | 3/39 (7.7%) | 4 | 3/38 (7.9%) | 4 |
| Laceration | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Ankle fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Procedural pain | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Foot fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Hip fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Spinal fracture | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Post lumbar puncture syndrome | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Upper limb fracture | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Hand fracture | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Skin injury | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Road traffic accident | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Arthropod bite | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Buttock injury | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Pelvic fracture | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Investigations | ||||||
| Platelet function test abnormal | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 1/38 (2.6%) | 1 |
| Alanine aminotransferase increase | 2/85 (2.4%) | 2 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Aspartate aminotransferase increa | 2/85 (2.4%) | 2 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| White blood cell count increased | 0/85 (0%) | 0 | 1/39 (2.6%) | 2 | 0/38 (0%) | 0 |
| Antiphospholipid antibodies posit | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Blood creatine phosphokinase abno | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Prostatic specific antigen increa | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Retinal function test abnormal | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Blood creatine phosphokinase incr | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Gamma-glutamyltransferase increas | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Blood glucose increased | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Blood uric acid increased | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Occult blood positive | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Anti-thyroid antibody positive | 1/85 (1.2%) | 2 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Blood alkaline phosphatase increa | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Blood creatinine abnormal | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Blood creatinine increased | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Blood urine | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Cystoscopy | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Glomerular filtration rate increa | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Mean cell volume abnormal | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Nuclear magnetic resonance imagin | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Platelet count decreased | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Prostate biopsy | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hyperkalaemia | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Gout | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Hyponatraemia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 0/85 (0%) | 0 | 3/39 (7.7%) | 3 | 0/38 (0%) | 0 |
| Pain in extremity | 1/85 (1.2%) | 1 | 2/39 (5.1%) | 2 | 0/38 (0%) | 0 |
| Musculoskeletal pain | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Groin pain | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Osteoarthritis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Spinal column stenosis | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Arthralgia | 2/85 (2.4%) | 2 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Osteoperosis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 2/38 (5.3%) | 2 |
| Arthritis | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Joint swelling | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Muscle injury | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Muscle spasms | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Muscle strain | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Bone lesion | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Haemarthrosis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Basal cell carcinoma | 1/85 (1.2%) | 1 | 2/39 (5.1%) | 2 | 1/38 (2.6%) | 1 |
| Nervous system disorders | ||||||
| Trigeminal neuralgia | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Aphasia | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Cervical radiculopathy | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Migraine | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Paresthesia | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Somnolence | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Headache | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Seizure | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Psychiatric disorders | ||||||
| Depression | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Sleep disorder | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Haematuria | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Micturition urgency | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Urinary incontinence | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Urinary retention | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Chromaturia | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| Prostatitis | 1/85 (1.2%) | 1 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Nasal congestion | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Nasal crusting | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Asthma | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Pulmonary mass | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Rhinitis allergic | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Sleep apnoea syndrome | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Hyperhidrosis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Decubitus ulcer | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Dermatitis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Pityriasis rosea | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Rash | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Seborrhoeic dermatitis | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Surgical and medical procedures | ||||||
| Catheter management | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Trigeminal nerve ablation | 0/85 (0%) | 0 | 1/39 (2.6%) | 1 | 0/38 (0%) | 0 |
| Ear tube insertion | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Tooth extraction | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Vasectomy | 0/85 (0%) | 0 | 0/39 (0%) | 0 | 1/38 (2.6%) | 1 |
| Endodontic procedure | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
| Vascular disorders | ||||||
| Peripheral venous disease | 1/85 (1.2%) | 1 | 0/39 (0%) | 0 | 0/38 (0%) | 0 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Dr. Bibiana Bielekova |
|---|---|
| Organization | National Institute of Allergy and Infectious Diseases, National Institutes of Health |
| Phone | (240) 669-2724 |
| bibi.bielekova@nih.gov |
- 090197
- 09-I-0197