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Clinical Trial Results:
A Double-blind, Placebo-controlled, Randomized, Multicenter Proof-of-principle Trial of Adjunctive Minocycline for Patients With Treatment Resistant Unipolar Major Depressive Disorder (MDD)

Summary
EudraCT number	2015-001456-29
Trial protocol	DE
Global end of trial date	07 Aug 2020

Results information
Results version number	v1(current)
This version publication date	21 May 2022
First version publication date	21 May 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Mino-TRD(OptiMD)

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Charité University Medicine Berlin

Sponsor organisation address

Hindenburgdamm 30, Berlin, Germany, 12203

Public contact

Charité - Campus Benjamin Franklin, Institut Klinik für Psychiatrie und Psychotherapie, +49 30450 517522, isabella.heuser@charite.de

Scientific contact

Charité - Campus Benjamin Franklin, Institut Klinik für Psychiatrie und Psychotherapie, +49 30450 517522, isabella.heuser@charite.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

07 Aug 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Aug 2020

Global end of trial reached?

Yes

Global end of trial date

07 Aug 2020

Was the trial ended prematurely?

Main objective of the trial

Change in the MADRS value from starting point (week 1) to last visit (week 7), with weekly visits Time point of determination of primary target parameters (objective): week 1-6, 7, 6 week after and 6 months after last visit

Protection of trial subjects

Routine lab safety measurements were performed in addition to clinical interviews, where AEs were assessed

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Aug 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 168

Worldwide total number of subjects

168

EEA total number of subjects

168

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

168

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 9 study centers in 1 country,7. Januar 2016 - 7. August 2020

Screening details

A total of 253 subjects entered the screening period, of whom 85 withdrew before randomization. The remaining 168 subjects were randomized.

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Minocycline

Arm description

Arm type

Experimental

Investigational medicinal product name

Minocycline Hydrochloride dihydrate

Investigational medicinal product code

10118-90-8

Other name

Udima

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Subjects Minocycline Hydrochloride dihydrate capsule orally for 7 weeks (daily, weekly...??)

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

6 weeks 2X2 200mg Placebo

Number of subjects in period 1	Minocycline	Placebo
Started	81	87
Completed	69	75
Not completed	12	12
Adverse event, serious fatal	1	1
Consent withdrawn by subject	6	2
Physician decision	3	2
N/A	-	4
Adverse event, non-fatal	1	1
Protocol deviation	1	2

Baseline characteristics

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Reporting group title

Minocycline

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Minocycline	Placebo	Total
Number of subjects	81	87	168
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	44.8 ± 13.6	47.3 ± 12.5	-
Gender categorical
Units: Subjects
Female	31	48	79
Male	50	39	89
MADRS
MADRS=Montgomery–Åsberg Depression Rating Scale
Units: Score
arithmetic mean (standard deviation)	26.4 ± 4.8	26.6 ± 5.1	-
HAMD-17
AM-D-17=Hamilton Depression Rating Scale
Units: Score
arithmetic mean (standard deviation)	20.0 ± 3.5	20.3 ± 3.5	-
BDI II
BDI-II=Beck Depression Inventory
Units: Score
arithmetic mean (standard deviation)	32.3 ± 9.0	32.9 ± 10.4	-
SCL-90-RGSI
SCL-90-R= Symptom Checklist-90-R
Units: Score
arithmetic mean (standard deviation)	68.7 ± 6.8	66.9 ± 6.9	-
CGI
GSI Global Severity Index
Units: Score
arithmetic mean (standard deviation)	4.8 ± 0.6	4.9 ± 0.7	-
TMT-A
TMT = trail making test
Units: Score
arithmetic mean (standard deviation)	34.7 ± 16.6	35.1 ± 14.3	-
TMT-B
Units: Score
arithmetic mean (standard deviation)	77.5 ± 32.7	76.1 ± 32.3	-
CRP
C-reactive protein
Units: milligram(s)/litre
arithmetic mean (full range (min-max))	1.21 (0.02 to 22.10)	0.6 (0.05 to 7.30)	-
SCL-PSDI
Positive Symptom Distress Index
Units: Score
arithmetic mean (standard deviation)	66.3 ± 4.9	66.1 ± 6.0	-
SCL-PST
Positive Symptom Total
Units: Score
arithmetic mean (standard deviation)	64.4 ± 6.6	62.2 ± 6.0	-

End points

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Reporting group title

Minocycline

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Change of MADRS baseline - week 7

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End point title

Change of MADRS baseline - week 7

End point description

End point type

Primary

End point timeframe

MADRS scores were assessed at baseline and throughout week 7, change in MADRS score was calculated for the 6 week treatment period

End point values	Minocycline	Placebo
Number of subjects analysed	69	75
Units: points
arithmetic mean (standard deviation)	17.6 ± 7.8	18.7 ± 9.0

Change of the MADRS sum score

Comparison groups

Minocycline v Placebo

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

t-test, 2-sided

Confidence interval

level

95%

Secondary: Post-treatment BDI

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End point title

Post-treatment BDI

End point description

BDI II = Beck’s depression inventory Version II

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	66	72
Units: Score
arithmetic mean (standard deviation)
BDI	21.6 ± 12.0	23.6 ± 13.2

No statistical analyses for this end point

Secondary: Post-treatment CGI

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End point title

Post-treatment CGI

End point description

clinical global impression scale

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	69	75
Units: Score
arithmetic mean (standard deviation)
CGI	3.9 ± 1.1	4.0 ± 1.2

No statistical analyses for this end point

Secondary: Post-treatment HAMD 6

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End point title

Post-treatment HAMD 6

End point description

HAMD = Hamilton Depression Rating Scale

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	69	71
Units: Score
arithmetic mean (standard deviation)
HAMD6	7.4 ± 3.5	7.6 ± 6.7

No statistical analyses for this end point

Secondary: Post-treatment HAMD 17

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End point title

Post-treatment HAMD 17

End point description

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	68	71
Units: Score
arithmetic mean (standard deviation)
HAMD 17	13.1 ± 5.9	14.2 ± 6.7

No statistical analyses for this end point

Secondary: Post-treatment SCL-90

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End point title

Post-treatment SCL-90

End point description

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	66	72
Units: Score
arithmetic mean (standard deviation)
GSI	62.3 ± 10.7	62.0 ± 10.1
PSDI	60.2 ± 8.3	60.2 ± 8.9
PST	60.5 ± 10.1	59.5 ± 8.9

No statistical analyses for this end point

Secondary: Post-treatment trail making test

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End point title

Post-treatment trail making test

End point description

End point type

Secondary

End point timeframe

6 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	69	74
Units: Score
arithmetic mean (standard deviation)
TMT-A	29.9 ± 12.2	30.4 ± 14.1
TMT-B	68.1 ± 27.6	68.8 ± 29.1

No statistical analyses for this end point

Secondary: Post-treatment Log CRP

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End point title

Post-treatment Log CRP

End point description

End point type

Secondary

End point timeframe

4 weeks

End point values	Minocycline	Placebo
Number of subjects analysed	66	69
Units: milligram(s)/litre
arithmetic mean (standard deviation)
CRP	1.77 ± 0.29	1.82 ± 0.28

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

6 weeks

Assessment type

Systematic

Dictionary name

own

Dictionary version

Reporting group title

Minocycline

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Minocycline	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 81 (7.41%)	8 / 87 (9.20%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Investigations
Colon-Ca; CEA- Increase
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumormarkerbefund
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
cheekbone fracture
subjects affected / exposed	1 / 81 (1.23%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
drunk bicycle accident
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vascular disorders
Zerebrale Aneurysmablutung
subjects affected / exposed	1 / 81 (1.23%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Eosinophilie
subjects affected / exposed	1 / 81 (1.23%)	0 / 87 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Cholezystektomie
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
biliäre Pankreatitis
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	3 / 81 (3.70%)	2 / 87 (2.30%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal behaviour
subjects affected / exposed	0 / 81 (0.00%)	1 / 87 (1.15%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Minocycline	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	67 / 81 (82.72%)	63 / 87 (72.41%)
Nervous system disorders
Headache
subjects affected / exposed	17 / 81 (20.99%)	27 / 87 (31.03%)
occurrences all number	33	43
Dizziness
subjects affected / exposed	15 / 81 (18.52%)	5 / 87 (5.75%)
occurrences all number	20	7
Tremor
subjects affected / exposed	3 / 81 (3.70%)	0 / 87 (0.00%)
occurrences all number	5	0
General disorders and administration site conditions
Tiredness
subjects affected / exposed	9 / 81 (11.11%)	6 / 87 (6.90%)
occurrences all number	11	9
Hyperhidrosis
subjects affected / exposed	3 / 81 (3.70%)	6 / 87 (6.90%)
occurrences all number	4	6
Gastrointestinal disorders
Dyspepsia/Indigestion
subjects affected / exposed	14 / 81 (17.28%)	14 / 87 (16.09%)
occurrences all number	25	19
Flatulence/Diarrhoea
subjects affected / exposed	12 / 81 (14.81%)	14 / 87 (16.09%)
occurrences all number	15	26
Nausea
subjects affected / exposed	8 / 81 (9.88%)	11 / 87 (12.64%)
occurrences all number	12	12
Skin and subcutaneous tissue disorders
Exanthem; Erythem, Akne
subjects affected / exposed	10 / 81 (12.35%)	10 / 87 (11.49%)
occurrences all number	11	11
Psychiatric disorders
Depression/Extracerbation
subjects affected / exposed	8 / 81 (9.88%)	9 / 87 (10.34%)
occurrences all number	10	10
Insomnia
subjects affected / exposed	2 / 81 (2.47%)	6 / 87 (6.90%)
occurrences all number	4	9
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 81 (7.41%)	6 / 87 (6.90%)
occurrences all number	6	6
Infections and infestations
flu-like symptoms
subjects affected / exposed	24 / 81 (29.63%)	13 / 87 (14.94%)
occurrences all number	30	16
Vaginal fungal infection
subjects affected / exposed	3 / 81 (3.70%)	1 / 87 (1.15%)
occurrences all number	5	1

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Double-blind, Placebo-controlled, Randomized, Multicenter Proof-of-principle Trial of Adjunctive Minocycline for Patients With Treatment Resistant Unipolar Major Depressive Disorder (MDD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change of MADRS baseline - week 7

Primary: Change of MADRS baseline - week 7

Secondary: Post-treatment BDI

Secondary: Post-treatment BDI

Secondary: Post-treatment CGI

Secondary: Post-treatment CGI

Secondary: Post-treatment HAMD 6

Secondary: Post-treatment HAMD 6

Secondary: Post-treatment HAMD 17

Secondary: Post-treatment HAMD 17

Secondary: Post-treatment SCL-90

Secondary: Post-treatment SCL-90

Secondary: Post-treatment trail making test

Secondary: Post-treatment trail making test

Secondary: Post-treatment Log CRP

Secondary: Post-treatment Log CRP

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Double-blind, Placebo-controlled, Randomized, Multicenter Proof-of-principle Trial of Adjunctive Minocycline for Patients With Treatment Resistant Unipolar Major Depressive Disorder (MDD)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change of MADRS baseline - week 7

Primary: Change of MADRS baseline - week 7

Secondary: Post-treatment BDI

Secondary: Post-treatment BDI

Secondary: Post-treatment CGI

Secondary: Post-treatment CGI

Secondary: Post-treatment HAMD 6

Secondary: Post-treatment HAMD 6

Secondary: Post-treatment HAMD 17

Secondary: Post-treatment HAMD 17

Secondary: Post-treatment SCL-90

Secondary: Post-treatment SCL-90

Secondary: Post-treatment trail making test

Secondary: Post-treatment trail making test

Secondary: Post-treatment Log CRP

Secondary: Post-treatment Log CRP

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Double-blind, Placebo-controlled, Randomized, Multicenter Proof-of-principle Trial of Adjunctive Minocycline for Patients With Treatment Resistant Unipolar Major Depressive Disorder (MDD)