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Phase III Trial of Coenzyme Q10 in Mitochondrial Disease

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ClinicalTrials.gov Identifier: NCT00432744
Recruitment Status : Completed
First Posted : February 8, 2007
Results First Posted : May 1, 2014
Last Update Posted : September 11, 2017
Sponsor:
Collaborators:
FDA Office of Orphan Products Development
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
University of Florida

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Mitochondrial Diseases
Interventions Drug: CoenzymeQ10
Drug: Placebo
Enrollment 24
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo First CoenzymeQ10 Frist
Hide Arm/Group Description

Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

Period Title: Months 0-6
Started 12 12
Completed 7 8 [1]
Not Completed 5 4
Reason Not Completed
Withdrawal by Subject             4             4
Too disabled to score             1             0
[1]
One patient in period 1 "other reason" for loss became too disabled to complete the 6 month test.
Period Title: Months 7 - 12
Started 7 8
Completed 6 7
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             0
Too disabled to score             0             1
Arm/Group Title Placebo First CoenzymeQ10 Frist Total
Hide Arm/Group Description

Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

Total of all reporting groups
Overall Number of Baseline Participants 12 12 24
Hide Baseline Analysis Population Description
This is the set of subjects that met all eligibility requirements
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants 12 participants 24 participants
9.0  (6.3) 7.5  (4.5) 8.3  (5.4)
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
<=18 years
12
 100.0%
12
 100.0%
24
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
Female
6
  50.0%
8
  66.7%
14
  58.3%
Male
6
  50.0%
4
  33.3%
10
  41.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants 12 participants 24 participants
United States 10 9 19
Canada 2 3 5
1.Primary Outcome
Title McMaster Gross Motor Function (GMFM 88)
Hide Description The McMaster Gross Motor Function is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. One of the links in this report is to the the GMFM scale and how it is scored. A link to the instrument is included.
Time Frame Taken at 6 and 12 Months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo First CoenzymeQ10 Frist
Hide Arm/Group Description:

Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

Overall Number of Participants Analyzed 6 8
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
-0.002
(-0.47 to 1.36)
-0.12
(-2.75 to 1.75)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo First, CoenzymeQ10 Frist
Comments Study intended to accrue 40 subjects, but only obtained 14 evaluable on this endpoint.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.95
Comments Two-sided Test
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Kendall's Tau B
Estimated Value .015
Confidence Interval (2-Sided) 95%
-0.44 to 0.48
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.23
Estimation Comments Positive value of Tau-B would favor CoQ.
2.Primary Outcome
Title Pediatric Quality of Life Scale
Hide Description The Pediatric Quality of Life Scale is a validated scale ranging from 0 to 100 (the higher the better). Since there was the possibility of a subject becoming totally disabled our FDA peer reviewed design called for its use as follows: If the subject completed both periods, the score was calculated as the difference in scores between the end of Period 2 (at 12 months) minus that at the end of Period 1 (6 months). If a subject became totally disabled, this difference was considered as plus infinity if it occurred in period 1 (Penalizes period 1), and minus infinity if it occurred in Period 2 (Penalizes period 2). The two treatments were compared via the Wilcoxon test, and the effect size was estimated using Kendall's Tau-B. This is interpreted in a similar manner to correlation with positive values favoring COQenzyme10 and negative values favoring placebo. Goggle "pedsQL and Mapi" to browse the copyrighted manual. A link to the instrument is included.
Time Frame At 6 and 12 Months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
7 subjects in each group were evaluable for this endpoint. The two subjects who became disabled are evaluable. One subject did not have period 2 Quality of Life data and is excluded.
Arm/Group Title Placebo First CoenzymeQ10 Frist
Hide Arm/Group Description:

Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

Overall Number of Participants Analyzed 7 7
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
-1.1
(-4.3 to 7.1)
-11.9
(-43.5 to 4.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo First, CoenzymeQ10 Frist
Comments Study intended to accrue 40 subjects, but only obtained 14 evaluable on this endpoint.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.18
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Kendall's Tau B
Estimated Value 0.30
Confidence Interval (2-Sided) 95%
-0.12 to 0.72
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.21
Estimation Comments A positive value would favor CoQ.
3.Primary Outcome
Title Non-parametric Hotelling T-square Bivariate Analysis of GMGF 88 and OPeds QOL.
Hide Description This is a multivariate analysis of the first two outcomes: Period 2 minus Period 1 GMFM88 and Peds Quality of Life, analyzed as follows: First, to be in the analysis, subjects must contribute at least one of these endpoints. Second, if the subject became totally disabled during period 1, the difference was defined as + infinity, (highest possible evidence favoring period 2), and if the subject became totally disabled in period 2, the subject was scored as - infinity (highest possible evidence favoring period 1). Period 2 minus period 1 differences were ranked form low to high with missing values scores at the mid-rank. The Hotelling T-square was computed on these ranks and the P-value was obtained from 100,000 rerandomizations as the fraction of rerandomizations with T-sq at least as large as that observed.
Time Frame end of 12 month minus end of 6 month difference.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Subjects contributes at least one difference (either GMFM or Peds QOL). Thirteen contributed both and one each was missing GMFM or Peds QOL.
Arm/Group Title Placebo First CoenzymeQ10 Frist
Hide Arm/Group Description:

Patients will be randomized to receive Placebo in Period #1 (Months 0-6) and CoenzymeQ10 given in Period #2( Months 7-12.)

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Patients will be randomized to receive CoenzymeQ10 in Period #1 (Months 0-6) and Placebo given in Period #2( Months 7-12.)

CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed.

Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group.

Overall Number of Participants Analyzed 7 8
Measure Type: Number
Unit of Measure: participants
7 8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo First
Comments The actual study was powered to have 40 participants but only 24 participated and of these only 15 had outcome data.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments The Hotelling T-sq=1.74 and 42% of the rerandomizations to groups of 7 and 8 had Hotelling T-sq of at least 1.74. This is the standard method for permutation tests. The large sample null is chi-sq with 2 df, which has a mean=2.
Method Non-parametric Hotelling T-square
Comments [Not Specified]
Time Frame AE's were collected from 10/2007 to 4/2012.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title CoenzymeQ10 Placebo
Hide Arm/Group Description CoenzymeQ10: CoenzymeQ10 will be given in 10 mg/kg daily up to 400 mg. Then a draw of CoQ10 troughs every three months will be performed. (Either in Period 1 or Period 2) Placebo: Placebo will be given in 10 mg/kg daily up to 400 mg. Then a draw of placebo troughs every three months will be performed. This treatment group will be treated as the active group. (Either in Period 1 or Period 2)
All-Cause Mortality
CoenzymeQ10 Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
CoenzymeQ10 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/19 (5.26%)      2/20 (10.00%)    
Musculoskeletal and connective tissue disorders     
Hospitalization for lumbar vertebrae fractures  1 [1]  0/19 (0.00%)  0 1/20 (5.00%)  1
Nervous system disorders     
Altered Mental State  1 [2]  0/19 (0.00%)  0 1/20 (5.00%)  1
Hospitalization for seizure activity  1 [3]  1/19 (5.26%)  1 0/20 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 10.0
[1]
Subject was involved in an accident in which two (2) lumber vertebrae were fractured
[2]
Not related to the study
[3]
Subject with MELAS; not related to study
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
CoenzymeQ10 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/19 (52.63%)      10/20 (50.00%)    
Blood and lymphatic system disorders     
Decreased White Blood Count  1  1/19 (5.26%)  1 0/20 (0.00%)  0
Low ANC Levels  1  0/19 (0.00%)  0 1/20 (5.00%)  1
Elevated Liver Enzymes  1  1/19 (5.26%)  1 1/20 (5.00%)  1
Ear and labyrinth disorders     
Ear Infection  1  1/19 (5.26%)  1 1/20 (5.00%)  1
Gastrointestinal disorders     
GI Issues  1  2/19 (10.53%)  2 5/20 (25.00%)  5
General disorders     
Nose Bleed * 1  0/19 (0.00%)  0 1/20 (5.00%)  1
Fatigue  1  1/19 (5.26%)  1 0/20 (0.00%)  0
Infections and infestations     
GTube Infection  1  1/19 (5.26%)  1 0/20 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Neuromusclar Changes  1  1/19 (5.26%)  1 1/20 (5.00%)  1
Nervous system disorders     
Mental Status Change  1  1/19 (5.26%)  1 0/20 (0.00%)  0
Skin and subcutaneous tissue disorders     
Rash  1  1/19 (5.26%)  1 0/20 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 10.0
The trial intended to accrual 40 subjects, but accrual was below expectations and the granting agency turned down a request for extended accrual.
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. Peter W Stacpoole
Organization: University of Florida
Phone: 352-273-9023
EMail: pws@ufl.edu
Publications:
Kerr DS. Treatment of congenital lactic acidosis: a review. Intern Pediatr, 1995;10:75-81.
Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00432744     History of Changes
Other Study ID Numbers: 1R01FD003032-01A1 ( U.S. FDA Grant/Contract )
R01FD003032-01A1 ( U.S. FDA Grant/Contract )
First Submitted: February 6, 2007
First Posted: February 8, 2007
Results First Submitted: April 11, 2014
Results First Posted: May 1, 2014
Last Update Posted: September 11, 2017