Primary ObjectiveThe primary objective of this study is to assess whether the antidepressant response to IV ketamine can be maintained by minocycline compared to placebo.Secondary ObjectivesThe secondary objectives of this study are:* To investigate…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
The primary efficacy endpoint will be the proportion of subjects who survive
relapse-free (among
responders) on Day 54 (Week 6) of the 6-week blinded treatment period.
A subject will be defined as *relapsed* if his/her MADRS total score has
returned to >= 30 after at least the
first dose administration of minocycline or placebo in the 6-week blinded,
treatment phase.
Secondary outcome
Major Secondary Endpoint
Ketamine non-responders: The change in MADRS total score from Day 12 (3 to 4
hours post dose) of the
12-day open-label treatment phase to end-of-study (Day 54).
Other Secondary Endpoints
* Change in the MADRS total score from baseline (Day 1 predose) during the IV
ketamine treatment phase (Days 1, 3, 5, 8, 10 and 12).
* Change in the MADRS total score from baseline (Day 1 predose) after the IV
ketamine treatment phase (Days 20, 27, 34, 41, 48, and 54).
* Response (reduction >= 50% in MADRS total score relative to baseline) rate
during the IV ketamine treatment phase (Days 1, 3, 5, 8, 10 and 12)
* Time to relapse (among responders) following completion of the IV ketamine
infusion schedule.
* Effects on Columbia Suicide Severity Rating Scale (C-SSRS)
EXPLORATORY INFLAMMATORY MARKER EVALUATION
Venous blood samples (2 x 10 mL samples per time point) will be collected for
the assessment of inflammatory markers (e.g., CRP, IL-6, IL-1β, TNF-α, MCP-1)
at the time points specified in the Time and Events Schedule. At the same
time-points, a venous blood sample (10 mL) will be collected for the extraction
of messenger RNA (mRNA) for transcriptomics. RNA samples will not be used for
genetic testing. Where appropriate consent is obtained, inflammatory marker
samples and RNA samples will also be stored for future research related to
inflammation and depression after the clinical study is completed (where local
regulations permit).
SAFETY EVALUATIONS
Regular assessments of safety and tolerability of the study medication (i.e.,
ketamine, minocycline,
minocycline-matching placebo), and assessment of suicidal ideation and behavior
using the C-SSRS, will
be made during the study as outlined in the Time and Events Schedule.
TREATMENT COMPLIANCE
Venous blood samples (4mL) will be collected as per Time and Events schedule in
order to assess
treatment compliance for minocycline. Samples will only be analyzed in case of
doubt of treatment
compliance of a subject based on any abnormalities observed in the study data
collected.
STATISTICAL METHODS
Due to the exploratory nature of this study, no adjustments for multiple
testing will be applied.
Background summary
Better treatment paradigms for major depressive disorder (MDD) are needed.
Ketamine, a racemate of R- (-)-ketamine and S-(+)-ketamine, is an approved
medication for the induction of general anesthesia and for use in addition to
other anesthetics. It is an anesthetic for diagnostic procedures and
short-lasting surgery. A number of small, published studies suggest that
intravenous (IV) ketamine may also have efficacy in subjects with
treatment-resistant depression (TRD), with an onset of antidepressant effect
within one day. However, after a single dose most subjects relapse within 1
week. The antidepressant response to ketamine can be prolonged by the
administration of multiple doses.
However, ketamine is best used under healthcare supervision and frequent
long-term use is associated with deleterious cognitive effects. Thus, ketamine
is difficult for regular and frequent administration. Therefore, it is
important to identify other therapeutic options that can prolong the duration
of symptom reduction induced by ketamine. Prior studies suggest that selective
serotonin reuptake inhibitors (SSRIs), mood stabilizers, and the
anti-glutamatergic drug riluzole are not sufficiently effective (Mathew et al
2010; Ibrahim et al., 2012). In this study, the aim is to investigate whether
the tetracycline antibiotic drug, minocycline, can maintain IV ketamine-induced
MDD symptom response. In all subjects, minocycline will be initiated at the
same time as ketamine in the initial open-label treatment phase. This way, it
is hoped that possible delays in the onset of effect of minocycline will
not/minimally interfere with the timeto- relapse that is measured during the
blinded treatment period.
Nonclinical and clinical studies suggest broad central nervous system (CNS)
activities for minocycline: modulation of glutamate-induced excitotoxicity,
antioxidant effects, and anti-inflammatory- and neuroprotective effects.
Because of these broad CNS activities and the realization that the affected
systems may play a role in the pathophysiology of depressive illness, several
studies have been initiated to investigate the effect of minocycline in mood
disorders. The CNS effects of minocycline resemble those of a novel class of
brain-penetrating P2X7 antagonists, so that proof-of-concept (POC) in this
study can guide the development of this class of compounds currently in
non-clinical development
Study objective
Primary Objective
The primary objective of this study is to assess whether the antidepressant
response to IV ketamine can be maintained by minocycline compared to placebo.
Secondary Objectives
The secondary objectives of this study are:
* To investigate the safety and tolerability of the administered study
medications (i.e., ketamine and
minocycline);
* To investigate the effect of minocycline on symptoms of depression in
ketamine non-responders.
Exploratory Objectives
The exploratory objective of this study is:
* To assess the relationship of inflammatory markers (e.g., C-reactive protein
[CRP], interleukin
[IL]-6, IL-1β, TNF-α, monocyte chemotactic protein [MCP]-1) and/or changes in
white blood
cell (WBC) RNA expression (transcriptomics) to response and relapse after
ketamine infusion.
Study design
This is a placebo-controlled, blinded, randomized study being conducted in up
to 80 male and female subjects, between 18 and 80 years of age (inclusive),
with MDD or Bipolar Depression (BPD) Type II.
The study has four sequential phases:
1) A screening phase of up to 3 weeks,
2) A 12-day open-label treatment phase during which all subjects will receive
ketamine and
minocycline,
3) A 6-week blinded OR optional open-label treatment phase:
a. For ketamine responders: A 6-week blinded treatment phase during which
subjects will be randomly assigned to receive minocycline or placebo in a 1:1
ratio
b. For ketamine non-responders: An optional 6-week open-label treatment phase
during
which subjects receive minocycline
4) A follow up phase: Subjects will have one End-of-Study visit.
The total study duration for each subject will be maximally 11 weeks. The end
of the study is defined as the date of the last study assessment of the last
subjects in the trial. Enrollment for the study will end when 42 eligible
subjects respond to ketamine on Day 12 (of the 12-day open-label treatment
phase) and are randomized to receive minocycline or placebo in the 6-week
blinded treatment phase
Intervention
12-Day Open-Label Treatment Phase
Subjects will be admitted to the study site on Day 1, 3, 5, 8, 10, and 12 for
study visits. Outpatient subjects may be discharged 4 hours after the start of
the ketamine infusion (i.e., 4 hours postdose) if there are no safety concerns.
Subjects cannot drive a car or operate machinery for 24 hours after receiving
ketamine.
All subjects will receive ketamine 0.5 mg/kg IV infusion over 40 minutes while
at the study site on Day 1, 3, 5, 8, 10, and 12, for a total of 6 doses (see
Dosage and Administration). In the evening of Day 1 (i.e., Day 1 PM), subjects
will orally self-administer minocycline 200 mg. Then,
starting the morning of Day 2 (i.e., Day 2 AM) through the morning of Day 12
(i.e., Day 12 AM), subjects will orally self-administer minocycline 100 mg bid.
A subject will be defined as a *ketamine responder* provided his/her MADRS
total score on Day 12,
performed at 3 to 4 hours post dose, shows a * 50% decrease in comparison to
baseline values (Day 1 predose). A subject will be defined as a *ketamine
non-responder* provided his/her MADRS total score on Day 12, performed at 3 to
4 hours post dose, shows a < 50% decrease in comparison to baseline values (Day
1 predose).
Study procedures (e.g., efficacy, safety, biomarker) that will be performed
during this treatment phase are described in the Time and Event Schedule.
6-Week Treatment Phase
Ketamine Responders (blinded, randomized)
Subjects that are *ketamine responders* will participate in a 6-week blinded,
randomized treatment phase. Study visits will be conducted on Days 20, 27, 34,
41, and 48. Study procedures (e.g., efficacy, safety,treatment compliance) that
will be performed at these visits are described in the Time and Event Schedule.
On Day 12 of the 12-day open-label treatment phase, 42 subjects will be
randomly assigned in a 1:1 ratio to receive either minocycline 100 mg or
placebo bid for 6 weeks. Subjects will orally self-administer minocycline 100
mg or placebo bid from the evening of Day 12 (i.e., Day 12 PM) through the
morning of Day 54 (i.e., Day 54 AM) or until relapse, whichever comes first. A
subject will be defined as *relapsed* if his/her MADRS total score has returned
to >= 30 after at least the first dose administration of minocycline or placebo
in this blinded phase. The subject and investigator will be blinded to
treatment allocation through study completion. The Sponsor of the study,
including dedicated sponsor personnel, will be unblinded.
Ketamine Non-Responders (optional, open-label)
Subjects that are *ketamine non-responders* will have the option to participate
in a 6-week open-label treatment phase. Study visits will be conducted on Days
20, 27, 34, 41, and 48. Study procedures (e.g., efficacy, safety, treatment
compliance) that will be performed at these visits are described in the Time
and Event Schedule. Subjects will orally self-administer minocycline 100 mg bid
from the evening of Day 12 (i.e., Day 12 PM) through the morning of Day 54
(i.e., Day 54 AM).
Study burden and risks
This is described in the patient information sheet at the section: "What are
the possible side effects'
Side Effects from Ketamine
Like all medicines ketamine can cause side effects, although not everyone gets
them. Side effects are normally dependent on the dose and how quickly the drug
is administered.
Ketamine can sometimes cause allergic symptoms (*anaphylaxis*) such as
breathing problems, swelling and rash and an increase in salivation. Some
people have vivid dreams, feel confused or behave irrationally while recovering
from anesthesia with ketamine.
The side effects of ketamine are classified on the basis of the frequency with
which they occur, as follows:
• Very common: >=1/10 (>10%)
• Common: >=1/100 and < 1/10 (>1% and <10%)
• Uncommon: >=1/1000 and < 1/100 (>0.1% and <1%)
• Rare: >=1/10.000 and < 1/1000 (>0.01% and <0.1%)
• Very rare: < 1/10.000 (<0.01%)
• Unknown
Immune system disorders
Rare Allergic reaction
Psychiatric disorders
Common Vivid dreams, dream-like feeling, nightmares, out of body experience,
feeling like you might pass out, and disrupted motor skills. These symptoms
will go away when the administration is stopped.
Nervous system disorders
Common Dizziness
Uncommon Jerky arm movements, which resemble a seizure (as a result of
increased muscle tension) and cross-eye.
Eye disorders
Common Blurred vision
Uncommon Double vision, increase in pressure in the eye
Heart / Vascular disorders
Common Increase in heart rate and blood pressure during administration period
Rare Irregular heart rate or decreased heart rate or low blood pressure
Respiratory, chest disorders
Common Increase pressure in the lungs and temporary slowing of breathing rate.
These typically happen with high doses.
Skin and subcutaneous tissue disorders
Uncommon Rash
Gastrointestinal disorders
Common Nausea and vomiting, increased saliva production
General disorders and administration site conditions
Common Change in taste (metallic taste, bitter taste), nasal congestion, change
in smell, sneezing
Uncommon nasal pain, bleeding, postnasal drip
Genitourinary Disorders
Rare pain or burning when you urinate
Investigations
Common Increase in blood pressure and increased heart rate (approx. 20% of the
normal rate is usual) due to anxiety
Misuse of ketamine has been reported in the past. Reports have indicated that
ketamine can cause various symptoms, including, but not limited to, flashbacks,
hallucinations, euphoria or dysphoria (*unhappiness*), anxiety, insomnia
(sleeplessness) or disorientation. Individuals with a history of drug misuse or
dependence can develop a dependency on ketamine.
You should not drive or operate machinery for at least 24 hours after
administration of the study drug. (See also under *What Do I Have To Do?*)
Side effects from Minocycline:
The following adverse reactions have been observed in patients receiving
tetracyclines (Minocycline is part of the class of antibiotics called
tetracyclines).
General Body as whole
Fever, discoloration of urine or stools or sweat
Allergic Reactions
(anaphylaxis, hypersensitivity): rash, blood spots,bruising and discolouring to
the skin (purpura), shock, death, flaky skin(exfoliative dermatitis), increase
in the number of white blood cells and oneor more of the following:
inflammation of the liver (hepatitis), inflammation of the lungs caused by an
infection (pneumonitis), inflammation of the kidneys, inflammation of the heart
muscle (myocarditis) or membrane around the heart (pericarditis). Fever,
swelling of the lymph nodes, swelling of the face, lips, tongue or throat.
Gastrointestinal disorders
feeling or being sick, diarrhoea, loss of appetite, underdevelopment of tooth
enamel, inflammation of the tongue, mouth or intestines, difficulty swallowing,
inflammation or ulceration of the gullet, indigestion, pseudomembranous colitis
(watery diarrhoea, fever and cramps).
Nervous system disorders
dizziness, headache, tingling or pins and needles in the hands and feet,
feeling of dizziness or spinning (vertigo), decreased sensitivity to touch,
fits, drowsiness
Liver and Kidney
inflammation of the liver (hepatitis), kidneys or pancreas (pancreatitis),
liver failure, jaundice (yellowing of theskin or whites of the eyes), abnormal
liver function test results, acute kidney failure.
Heart disorders
inflammation of the heart muscle (myocarditis) or membrane around the heart
(percarditis)
Blood disorders
increased levels of urea in the blood, blood vessel inflammation, changes in
the numbers and types of your blood cells. If you notice increased bruising,
nosebleeds, sore throats, infections, excessive tiredness, breathlessness on
exertion or abnormal paleness of the skin, you should tell your doctor who may
want you to have a blood test
Respiratory, chest disorders
inflammation of the lungs caused by an infection (pneumonitis), cough, increase
in the number of white blood cells in the lungs
Skin and subcutaneous tissue disorders
a change in colour of the skin, nails, teeth, mucous membrane of the mouth,
bones, thyroid, eyes, secretions including breast milk, tears or sweat
(hyperpigmentation)
Immune system disorders
fever, itchy skin rash, rash, joint pain (arthralgia), inflammation (arthritis)
stiffness or swelling of joints, increase in the number of white blood cells
(serum sickness like syndrome). presence of antinuclear antibodies in the
blood, joint pain (arthralgia), inflammation (arthritis) stiffness or swelling
of joints and one or more of the following: fever, muscle pain (myalgia),
inflammation of the liver (hepatitis), skin rash, inflammation of blood vessels
General disorders
fever, inflammation of the heart muscle (myocarditis) or membrane around the
heart (percarditis), impaired hearing, ringing in the ears, thrush around your
bottom, genital area or mouth, inflammation of male genitals, changes in
thyroid function, systemic lupus erythematosus (SLE), if you already suffer
from SLE Minocycline tablets may make your condition worse.
The adverse events more commonly seen in overdose are dizziness, nausea, and
vomiting.
No specific antidote for minocycline is known.
In case of overdosage, minocycline should be discontinued and patients treated
symptomatically, with supportive measures. Minocycline is not removed in
significant quantities by hemodialysis or peritoneal dialysis.
Side effects from tests:
• Blood draw: Taking blood may cause bruising at the place where the needle
goes into the skin. Fainting, and in rare cases infection, may occur.
• ECG Risk: There is generally no risk with having an ECG. The sticky patches
may pull your skin or cause redness or itching.
• An infusion may cause swelling of the vein by a blood clot. The study doctor
and/or the study team is trained to treat such a reaction.
There may be risks with ketamine and Minocycline that are not yet known.
Sometimes during a study, the Sponsor may learn new facts about the study drugs
or treatments. It is possible that this information might make you change your
mind about being in the study. If new information is discovered, your study
doctor will tell you about it right away
dr. Paul Janssenweg 150
Tilburg 5026RH
NL
dr. Paul Janssenweg 150
Tilburg 5026RH
NL
Listed location countries
Age
Inclusion criteria
- Diagnostic criteria for moderate to severe major depressive disorder (MDD), without mood incongruent psychotic features, or Bipolar Disorder Type II ;- Patients should have an Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30) total score >= 34 at Screening and at Day 1 (predose) ;- Patients with major depressive disorder should have failed at least two adequate treatment courses (dose and duration) with antidepressant therapy, one of which is in the current episode ;- Patients should not have received electroconvulsive therapy (ECT) in the current episode but could be those for whom ECT is considered ;- Patients with bipolar depression (BPD) Type II must have been taking a stable dose of a mood-stabilizing medication (e.g., lithium, valproate, carbamazepine, lamotrigine, antipsychotic agents) for at least 4 weeks, dosed clinically to target the therapeutic range ;- Patients currently taking an antidepressant(s) must have received at least 2 weeks of stable antidepressant therapy at the time of Screening ;- Doses of current antidepressant therapies should remain the same for the duration of the study ;- Women must be postmenopausal, surgically sterile, or if heterosexually active, practicing a highly effective method of birth control ;- Men who are heterosexually active with a woman of childbearing potential must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
Exclusion criteria
- Has a current DSM-IV axis I diagnosis other than MDD or BPD Type II at screening (except for co-morbid anxiety disorders) ;- Has a diagnosis of substance abuse or dependence within 6 months prior to screening evaluation (nicotine and caffeine dependence are not exclusionary) ;- Patient is currently taking > 4 psychotropic medications at Day 1 (predose) ;- Has an autoimmune disorder such as Crohn*s disease, rheumatoid arthritis, psoriasis currently treated with/requiring treatment with immunomodulatory therapies ;- Has any significant cardiovascular, respiratory, neurologic, renal, hepatic, endocrine, immunologic diseases, glaucoma, hypothyroidism or hyperthyroidism based on screening examination ;- Has uncontrolled hypertension (diastolic blood pressure >= 90 mmHg), despite diet, exercise or a stable dose of an allowed antihypertensive treatment, at Screening or Day 1 (predose) ;- Has planned vaccination within 2 weeks prior to the first dose of study medication through 2 weeks after the last dose of study medication ;- Has an active infectious disease/current infection ;- Has known allergies, hypersensitivity, or intolerance to minocycline or ketamine or its excipients ;- Has contraindications to the use of minocycline or ketamine per local prescribing information
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002954-21-NL |
| ClinicalTrials.gov | NCT01809340 |
| CCMO | NL45242.056.13 |