Clinical Trial Results:
Double blind placebo controlled randomized intervention study to validate the beneficial effect of hydrocortisone on dexamethasone-induced neurobehavioral side effects in pediatric acute lymphoblastic leukemia
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Summary
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EudraCT number |
2017-002738-22 |
Trial protocol |
NL |
Global end of trial date |
27 Mar 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
07 Sep 2022
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First version publication date |
07 Sep 2022
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Other versions |
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Summary report(s) |
Reason for late posting of results |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
62388
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
Netherlands Trial Register: NL6507 (NTR6695) | ||
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Sponsors
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Sponsor organisation name |
Princess Máxima Center for Pediatric Oncology
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Sponsor organisation address |
Heidelberglaan 25, Utrecht, Netherlands, 3584 CS
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Public contact |
M.M. van den Heuvel-Eibrink, Princess Máxima Center for Pediatric Oncology, 31 08809727007, m.m.vandenheuvel-eibrink@prinsesmaximacentrum.nl
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Scientific contact |
M.M. van den Heuvel-Eibrink, Princess Máxima Center for Pediatric Oncology, 31 08809727007, m.m.vandenheuvel-eibrink@prinsesmaximacentrum.nl
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Apr 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
25 Nov 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Mar 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To validate that addition of physiological doses of hydrocortisone to standard dexamethasone treatment reduces side effects in acute lymphoblastic leukemia patients who suffer from clinically relevant dexamethasone-induced neurobehavioral problems.
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Protection of trial subjects |
The risk-benefit analysis for this study showed a favorable risk profile. The IMP that was studied is hydrocortisone, given in a physiological dose, NOT in a pharmacological dose. No side effects were
expected in this physiological dose. In addition, we previously performed preclinical in vitro and ex vivo studies to prove that adding hydrocortisone to treatment will not have any negative effects on the efficacy of dexamethasone and prednisone regarding cytotoxicity on leukemic cells. Since we did not expect major risks, we did not install a data and safety monitoring board (DSMB) for this study.
Safety assessments consisted of collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug. This included the regular assessment of the patient's
physical condition and performance status.
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Background therapy |
This study is a double blind placebo controlled randomized trial with cross-over design. Patients are included if they experience clinically significant dexamethasone-induced neurobehavioral problems. These patients received the IMP (hydrocortisone) or placebo during 4 periods of a 5-day dexamethasone treatment during maintenance therapy. All children were randomized to either start with dexamethasone + IMP or dexamethasone + placebo. After two courses (with a washout period of 2 weeks and 2 days between each period) cross over took place. The IMP was hydrocortisone suspension, given orally in a physiological dose of 10 mg/m2/day. Patients used the hydrocortisone solution (1mg/ml) or placebo (equal in appearance and taste) 3 times per day in a 5:3:2 ratio (circadian rhythm). Timing of intake: first dose after awakening. Second dose between 12am and 1pm, the third dose between 6pm and 8 pm. 52 patients were randomized to answer our primary objective. However, in total 105 patients were included in our trial to be able answer our secondary objectives as well. | ||
Evidence for comparator |
NA | ||
Actual start date of recruitment |
17 May 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 105
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Worldwide total number of subjects |
105
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EEA total number of subjects |
105
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
90
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Adolescents (12-17 years) |
15
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment took place between 17 May 2018 (first inclusion) and 27 March 2021 (last patient last visit) in the Princess Máxima Center in Utrecht, The Netherlands. | |||||||||||||||
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Pre-assignment
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Screening details |
164 out of 278 ALL patients were eligible. 106 gave informed consent, 1 patient entered twice. 58 refused for these reasons: - Burden/effort n=17 - No time n=10 - Few side effects: n=10 - Child refuses: n=5 - Too many studies n=3 - Not interested n=5 - Other n=5 - Unknown n=3 Of the 105 unique patients, 52 were included in our RCT. | |||||||||||||||
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Period 1
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Period 1 title |
Baseline measurement
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||
Blinding implementation details |
Blinding was only used in the RCT (the period after baseline measurement)
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Start hydrocortisone | |||||||||||||||
Arm description |
Patients who started with hydrocortisone during the RCT with cross-over design. After two courses of hydrocortisone, cross over to placebo took place. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Hydrocortisone
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Investigational medicinal product code |
H02AB09 (CAS 50-23-7)
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Other name |
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Pharmaceutical forms |
Oral solution in bottle
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/m2/day. Patients used hydrocortisone (1mg/ml) 3 times per day in a circadian rhythm: 5 mg/m2 in the morning, 3 mg/m2 in the afternoon and 2 mg/m2 in the evening.
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Arm title
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Start placebo | |||||||||||||||
Arm description |
Patients who started with placebo during the RCT with cross-over design. After two courses of placebo, cross over to hydrocortisone took place. | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
NA
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Other name |
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Pharmaceutical forms |
Oral solution in bottle
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/m2/day. Patients used the placebo in exactly the same way as the IMP: 5 mg/m2 in de morning, 3 mg/m2 in the afternoon and 2 mg/m2 in the evening.
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Arm title
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No intervention | |||||||||||||||
Arm description |
Patients who did not have clinically significant dexamethasone-induced neurobehavioral problems (defined as a rise of 5 or more point on the Strengths and Difficulties Questionnaire (SDQ) Total Difficulties Score after 5 days of dexamethasone treatment) did not enter the randomized controlled trial. Also patients who only completed the baseline (dexamethasone-only) measurements after our RCT closed. | |||||||||||||||
Arm type |
No intervention | |||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 2
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Period 2 title |
Randomized Controlled Trial (n=52)
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Is this the baseline period? |
No | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||||||||
Blinding implementation details |
Patients were allocated to start with hydrocortisone or placebo using the method of a prefixed randomization list. This randomization list was prepared by the Princess Maxima Center pharmacy, independent of the clinical investigators. Both the IMP (hydrocortisone) and placebo were produced by the A15 pharmacy and distributed through the Princess Maxima Center pharmacy.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Hydrocortisone | |||||||||||||||
Arm description |
All patients in the RCT received two courses of hydrocortisone (cross-over design). | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Hydrocortisone
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Investigational medicinal product code |
H02AB09 (CAS 50-23-7)
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Other name |
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Pharmaceutical forms |
Oral solution in bottle
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/m2/day. Patients used hydrocortisone (1mg/ml) 3 times per day in a circadian rhythm: 5 mg/m2
in the morning, 3 mg/m2 in the afternoon and 2 mg/m2 in the evening.
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Arm title
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Placebo | |||||||||||||||
Arm description |
All patients in the RCT received two courses of placebo (cross-over design) | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
NA
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Other name |
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Pharmaceutical forms |
Oral solution in bottle
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg/m2/day. Patients used the placebo in exactly the same way as the IMP: 5 mg/m2 in de morning, 3 mg/m2 in the afternoon and 2 mg/m2 in the evening.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: After the baseline (first) period, only patients with clinically relevant dexamethasone-induced neurobehavioral problems were included in the subsequent period. Patients under the category 'no intervention' did not enter the RCT, therefore the number of subjects starting the RCT is not consistent with the total number completing the preceding period. |
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Baseline characteristics reporting groups
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Reporting group title |
Start hydrocortisone
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Reporting group description |
Patients who started with hydrocortisone during the RCT with cross-over design. After two courses of hydrocortisone, cross over to placebo took place. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Start placebo
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Reporting group description |
Patients who started with placebo during the RCT with cross-over design. After two courses of placebo, cross over to hydrocortisone took place. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
No intervention
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Reporting group description |
Patients who did not have clinically significant dexamethasone-induced neurobehavioral problems (defined as a rise of 5 or more point on the Strengths and Difficulties Questionnaire (SDQ) Total Difficulties Score after 5 days of dexamethasone treatment) did not enter the randomized controlled trial. Also patients who only completed the baseline (dexamethasone-only) measurements after our RCT closed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Start hydrocortisone
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Reporting group description |
Patients who started with hydrocortisone during the RCT with cross-over design. After two courses of hydrocortisone, cross over to placebo took place. | ||
Reporting group title |
Start placebo
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Reporting group description |
Patients who started with placebo during the RCT with cross-over design. After two courses of placebo, cross over to hydrocortisone took place. | ||
Reporting group title |
No intervention
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Reporting group description |
Patients who did not have clinically significant dexamethasone-induced neurobehavioral problems (defined as a rise of 5 or more point on the Strengths and Difficulties Questionnaire (SDQ) Total Difficulties Score after 5 days of dexamethasone treatment) did not enter the randomized controlled trial. Also patients who only completed the baseline (dexamethasone-only) measurements after our RCT closed. | ||
Reporting group title |
Hydrocortisone
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Reporting group description |
All patients in the RCT received two courses of hydrocortisone (cross-over design). | ||
Reporting group title |
Placebo
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Reporting group description |
All patients in the RCT received two courses of placebo (cross-over design) | ||
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End point title |
Neurobehavioral problems | ||||||||||||
End point description |
To answer our primary aim, we used the Dutch version of the parent-reported Strengths and Difficulties Questionnaire (SDQ). This 25-item questionnaire assesses psychological adjustment of children and youths and provides five subscales: emotional symptoms, conduct problems, hyperactivity and inattention, peer relationship problems and prosocial behavior. The Total difficulties score is the sum of the first four subscale scores (i.e. without prosocial behavior). A higher SDQ Total difficulties score reflects more problems. Like in our previous and current study a change of ≥5 points was considered clinically relevant. The effect of hydrocortisone was assessed by comparing the difference in SDQ scores of intervention day one and day five (delta score) of two consecutive hydrocortisone periods with two consecutive placebo periods.
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End point type |
Primary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
102
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
-2.05
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-6 | ||||||||||||
upper limit |
1.9 | ||||||||||||
| Notes [1] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 51 patients in our analyses, but these patients had 102 measurements. |
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End point title |
Objective sleep problems | ||||||||||||
End point description |
Children wore a wrist-worn actigraph (ActiGraph wGT3X-BT, Pensacola, FL, USA) for seven consecutive days twice: once during hydrocortisone and once during placebo. The parent kept an additional sleep-diary to document bedtimes, time of awakening and removal periods. The Sadeh algorithm was used to generate sleep outcomes. Total sleep time is reported.
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End point type |
Secondary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
6.88
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-7.26 | ||||||||||||
upper limit |
21.01 | ||||||||||||
| Notes [2] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 39 patients in our analyses, but these patients had 78 measurements. |
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End point title |
Subjective sleep | ||||||||||||
End point description |
To assess subjective sleep quality and sleep disturbances, we used the Sleep Disturbance Scale for Children (SDSC). This questionnaire contains 26 items and yields six subscales and a Total sleep score: a higher score reflects more problems. The effect of hydrocortisone was assessed by comparing the difference in SDSC scores of intervention day one and day five (delta score) of one hydrocortisone period with one placebo period.
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End point type |
Secondary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
84
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Analysis specification |
Pre-specified
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Analysis type |
other [3] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
-1.96
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-9.27 | ||||||||||||
upper limit |
5.35 | ||||||||||||
| Notes [3] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 42 patients in our analyses, but these patients had 84 measurements. |
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End point title |
Eating and hunger satiety | ||||||||||||
End point description |
To measure dexamethasone induced eating and hunger satiety we used an Eating Thermometer (ET): a visual analogue scale to indicate hunger. The scale ranged from 0 (no hunger at all) to 10 (terrible hunger). The effect of hydrocortisone was assessed by comparing the difference in thermometer score of intervention day one and day five (delta score) of one hydrocortisone period with one placebo period.
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End point type |
Secondary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
76
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
1.25
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.1 | ||||||||||||
upper limit |
3.6 | ||||||||||||
| Notes [4] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 38 patients in our analyses, but these patients had 76 measurements. |
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End point title |
Quality of Life | ||||||||||||
End point description |
The Pediatric Quality of Life Inventory (PedsQL), a 21- (for toddlers) or 23-item questionnaire, was used to assess health-related quality of life (HRQoL). A higher score reflects a better HRQoL in the child. The effect of hydrocortisone was assessed by comparing the difference in PedsQL scores of intervention day one and day five (delta score) of one hydrocortisone period with one placebo period.
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End point type |
Secondary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
82
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
3.25
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-13.69 | ||||||||||||
upper limit |
20.2 | ||||||||||||
| Notes [5] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 41 patients in our analyses, but these patients had 82 measurements. |
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End point title |
Parental distress | ||||||||||||
End point description |
We used the Distress Thermometer for parents (DT-P) to assess parental distress.21 Parents were asked to rate their overall distress from 0 (no distress) to 10 (extreme distress). The effect of hydrocortisone was assessed by comparing the difference in DT-P scores of intervention day one and day five (delta score) of one hydrocortisone period with one placebo period.
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End point type |
Secondary
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End point timeframe |
Measurement for the RCT (n=52) took place between May 17, 2018 and August 5, 2020.
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Statistical analysis title |
Repeated measurement analysis | ||||||||||||
Statistical analysis description |
Due to the presence of repeated measures in our study design, a generalized mixed model was estimated to study the effect of therapy on all outcomes. Age, sex, start group (hydrocortisone/placebo), week of maintenance treatment, concomitant asparaginase treatment (yes/no), whether mother or father completed the questionnaire and an interaction term between intervention and time (maintenance week) were included in the models.
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Comparison groups |
Hydrocortisone v Placebo
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Number of subjects included in analysis |
80
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Analysis specification |
Pre-specified
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Analysis type |
other [6] | ||||||||||||
Method |
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Parameter type |
estimated effect | ||||||||||||
Point estimate |
0.62
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2.23 | ||||||||||||
upper limit |
3.46 | ||||||||||||
| Notes [6] - Due to the cross-over design, hydrocortisone and placebo could be compared within patients in a repeated measurement model. We only included 40 patients in our analyses, but these patients had 80 measurements. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse event reporting took place between May 17, 2018 and August 5, 2020.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5
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Reporting groups
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Reporting group title |
Hydrocortisone
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Reporting group description |
Adverse events of 51 patients during hydrocortisone treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Adverse events of 52 patients during placebo treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Apr 2018 |
Addition of several laboratory measurements in blood. Modification of number and timing of blood sampling. Addition of the 'time to rise from the floor' test. Addition of an alternative bioelectrical impedance analysis device. |
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18 Feb 2019 |
Addition of two exclusion criteria. Addition of muscle strength measurement. Possibility to start during concomittant asparaginase treatment. Possibility to visit patients at home. |
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28 Sep 2020 |
Continuation of the study after closure of the RCT to answer secondary research questions. Addition of short sarcopenia questionnaire. Addition of measurement from residual blood. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
