A study of the safety and effect of food on absorption of KCL-286 in healthy men
| ISRCTN | ISRCTN12424734 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12424734 |
| EudraCT/CTIS number | 2018-000076-15 |
| Secondary identifying numbers | CRC385 |
- Submission date
- 19/06/2018
- Registration date
- 18/07/2018
- Last edited
- 18/07/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Background and study aims
There are currently no effective treatments for spinal cord injuries (SCIs), which can result in loss of feeling and control of the body below the level of the spinal cord injury. We have discovered KCL-286, which stimulates nerve regrowth in studies in rats. This study is the first test of KCL-286 in humans and aims to investigate whether it is safe and can be tolerated in humans. If it is safe, it will be tested in men with a type of spinal cord injury in which the nerve has been pulled away from the spinal cord to see if it can improve feeling and control of the affected body parts.
Who can participate?
Healthy men aged 19-45 years who are not underweight or obese.
What does the study involve?
The study is in two parts. In the first part, the participants will receive a single dose of KCL-286 or dummy treatment, allocated at random. They will be monitored closely to see if there are any side effects. If the single dose is considered safe, some participants will be randomly allocated to two groups. One group will take KCL-286 after fasting overnight and the other group will take KCL-286 after a high-fat breakfast. This is to investigate the effect of food on how the drug is handled within the body.
In the second part of the study, the participants will take 7 doses of KCL-286 or dummy treatment over 7 or 14 days. This is to investigate whether repeated doses of the drug are safe and whether there are side effects.
What are the possible benefits and risks of participating?
[Not provided at time of registration]
Where is the study run from?
Kings College London, UK
When is the study starting and how long is it expected to run for?
January 2018 to September 2021
Who is funding the study?
The Medical Research Council
Who is the main contact?
Professor Jonathan Corcoran
jonathan.corcoran@kcl.ac.uk
Contact information
Prof Jonathan Corcoran
Public
Public
Guy's Campus
London
SE1 1UL
United Kingdom
Study information
| Study design | Prospective Phase I double-blind randomised placebo-controlled dose-escalating study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Other |
| Participant information sheet | Not available in web format, please use the contact details below to request a participant information sheet |
| Scientific title | A Phase I, prospective, double-blind, randomised, placebo-controlled, dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending oral doses of KCL-286 and the effects of food in healthy male participants |
| Study acronym | KCL-286-01-Phase1 |
| Study objectives | KCL-286 is a retinoic acid receptor beta (RARβ) agonist being developed to treat traumatic nerve injury. The primary indication is the treatment of avulsed nerve roots of the brachial plexus. The nerves in the body originate from the spinal cord as spinal nerve roots. The ventral or motor roots connect to muscles and the dorsal or sensory roots convey sensory impulses from the periphery. Trauma to the nerve roots (typically in road traffic accidents) can result in the nerve roots being torn or avulsed from the spinal cord (SC). Such injury leads to degeneration of nerve fibres, death of nerve cells and a breakdown of connections within the SC. This is in effect a SC injury and it has a serious effect on central nervous connections and networks, with the development of a glial scar in the SC. Disintegration of the shorter SC parts of sensory neurons with degeneration of most of the motoneuron nerve fibres and a “dying back” of these neurites within the spinal cord follows from this trauma. Within a few weeks after such injury there will be an increasing death of neurons within the spinal cord affecting both, motor and sensory, as well as autonomic nerve cells. The functional consequence of such injury is “lower motoneuron syndrome” with flaccid muscle paralysis and eventual muscle atrophy and autonomic paralysis, including dysfunctional internal organs, as well as sensory impairments and, most disturbing, severe, almost unbearable chronic pain. Avulsion of sensory nerve roots induces a loss of SC dorsal horn neurons and interferes with sensory connections. This interference is thought to cause the classical central pain syndrome associated with root avulsion, possibly through loss of inhibition from peripheral sensory neurons. The nerve root traction injuries, which in the adult classically occur in motorbike accidents, affect mainly the complicated nerve formations called nerve plexa which innervate the limbs and are centrally connected to the SC through nerve ventral and dorsal roots. The brachial plexus which innervates the upper extremity is little protected from traction forces due to the loose suspension of the shoulder girdle and is easily injured when for instance a motorcyclist comes off the bike and the shoulder is impacted. The lumbosacral plexus innervating the lower extremity is more protected in the bony pelvis and fewer injuries occur. Plexus injuries are caused in serious road traffic accidents or violent acts. Brachial plexus injuries occur in 1.2% of polytrauma victims. About 70% of severe brachial plexus lesions have root avulsion injuries affecting over 1000 cases in the UK annually (Midha, 1997). Attempts to manage such injuries must involve maintenance of SC nerve cells and regeneration of nerve fibres within the spinal cord, i.e. central nervous regeneration. Root avulsion has been associated with an overall poor clinical outcome. Today, most patients are not treated at all or receive non-curative palliative procedures which do not give acceptable functional return or pain alleviation. Medullary implantation of peripheral nerve grafts or re-implantation of avulsed ventral or motor roots into the SC, if performed early after the injury, can curtail some neuronal loss and promote some regrowth of new motor or autonomic axons through SC tissue (central nerve fibre regeneration) and further into the peripheral nerves. Such SC surgery has long since been a routine procedure at centres in London and Stockholm. However, it has not been possible to reconstruct avulsed dorsal or sensory roots as these nerve fibres are prevented or inhibited from entering into the spinal cord most likely by the formation of glial scar tissue. The outcome from medullary reconstruction of motor neurons, results only in muscle activity among proximal arm and shoulder muscles with some alleviation of pain. There is, however, not any sensory return as only ventral or motor roots are reconnected to the SC. Most likely because of absence of sensory function the muscle activity and the movements restored are abnormal and sometimes not of any benefit. There are synkinesis and antagonistic muscle contractions which disturb the use of the arm. A medication that offers the chance of restoring sensory functions after root avulsion is necessary, to improve not only sensation, but also appropriate muscle and locomotor function, and most importantly alleviate the classical and excruciating root avulsion pain, which dominates the lives of many victims of root avulsion. Medication that improves the motor function following re-implantation of the ventral or motor roots would also be of potentially significant benefit to patients (Adams, 2007). Evidence from the animal work is that KCL-286 inhibits the formation of the glial scar tissue and, in the absence of this barrier, allows the re-implanted nerves to grow and make connections. In addition, KCL-286 appears to facilitate the RARβ signalling that is required for retinoid mediated neurite outgrowth of neurons, thus allowing the nerves to grow back. A full non-clinical development programme has been conducted including animal toxicology studies (with toxicokinetics) of up to 28 days in rats and dogs. The only significant toxicity seen in rats was related to premature closure of growth plates, which is not relevant to the human target population who will be adults whose growth plates will have closed at puberty. In dogs, cutaneous findings including reddening of the ears, gums and muzzle, decreased activity, dilated pupils, skin exfoliation and rash were observed (Teelmann, 1989). The findings are consistent with the known pharmacology of retinoids and are not considered to be different from the toxicity of retinoids currently on the market for other conditions. Further details are provided in the investigator’s brochure (IB). The proposed study is a first in human study, to be undertaken in healthy male participants, it is an adaptive design to investigate the safety and pharmacokinetics of single and multiple doses of KCL-286 administered orally and to assess the effect of food on the pharmacokinetics of KCL-286. The study is being conduct in males only due to the potential teratogenic effects of retinoids and the main indication of brachial plexus injury occurs almost exclusively in males. |
| Ethics approval(s) | London-Surrey Borders Research Ethics Committee, 09/05/2018, 18/LO/0460 |
| Health condition(s) or problem(s) studied | Avulsed nerve roots of the brachial plexus |
| Intervention | The study comprises 2 parts: Part A employs a single ascending dose (SAD) design with a separate food interaction (FI) arm for one cohort, and Part B employs a multiple ascending dose (MAD) design. Part A SAD will have up to 8 cohorts (S1 to S8). S1 and S2 will have 4 participants (3 active and 1 placebo in each cohort). The first 2 participants in S1 and S2 will be dosed at least 24 hours apart. If well tolerated the remaining 2 participants will be dosed together on the following day. For the subsequent cohorts there will be 8 participants; this will include sentinel dosing of the first 2 participants (1 active, 1 placebo) in each cohort with the remainder of the cohort (n=6; 5 active and 1 placebo) being dosed at least 24 hours later. Part A FI will include 8 participants (all on active treatment – no sentinel participants) who will be randomised in a two-way crossover study. One of the treatment periods will be fasted and the other will be administered after a high-fat breakfast. There will be at least 7 days or 5 half-lives (whichever is longer) between treatment periods. Part B MAD will have 4 cohorts (M1 to M4) of 8 participants (6 active and 2 placebo). There will be up to 4 dose levels which will be administered either daily for 7 days or every other day to cover 7 doses. There will be sentinel dosing of 2 participants (1 active and 1 placebo) in each cohort with the remaining participants in each cohort being dosed after the sentinel participants have received at least 4 doses. Safety and interim plasma pharmacokinetic data will be reviewed at the Safety Data Review Meetings during Part A and Part B prior to the commencement of the next dose cohort in each part. The starting dose to be used and whether it will be administer daily or on alternate days in Part B will be based on the safety, pharmacokinetic and pharmacodynamics data from Part A (SAD and FI). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | KCL-286 |
| Primary outcome measure | 1. Incidence and severity of adverse events up to 48 hours after the last dose 2. Incidence of serious adverse events up to 48 hours after the last dose 3. Change from baseline in vital signs (Heart rate, blood pressure, oral temperature and respiratory rate) measured pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the dose 4. Depression assessed using PHQ-9 questionnaire at 48 h post-dose 5. Anxiety assessed using GAD-7 questionnaire at 48 h post-dose 5. Change from baseline in laboratory data, including haematology tests (haemoglobin, hematocrit, white blood cells and platelets) and blood chemistry (alanine aminotransferase [ALT], albumin, alkaline phosphatase, aspartase aminotransferase, blood urea nitrogen [BUN], calcium, chloride, creatinine, glucose, glycosylated haemoglobin [Hb1Ac], potassium, sodium, thyroid stimulating hormone [TSD], thyroxine, total bilirubin, lipids, urea and electrolytes, creatinine and liver function tests [LFTs]) 1 day pre-dose and 24 h post-dose 6. Change from baseline in 12-lead ECGs performed after resting for approximately 10 minutes in the semi-recumbent position pre-dose and at 0.5, 1, 2, 4, 8, 12, 24 and 48 h post-dose |
| Secondary outcome measures | 1. Plasma and urine concentration-time profiles assessed using blood samples taken pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the dose and urine collected pre-dose and throughout the study up to 48 h post-dose 2. Plasma and urine pharmacokinetic parameters, including but not limited to Cmax, Tmax, AUC, half-life, fraction eliminated unchanged in urine and renal clearance, as data permit, using blood samples taken pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the dose and urine collected pre-dose and throughout the study up to 48 h post-dose |
| Overall study start date | 01/01/2018 |
| Completion date | 30/09/2021 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Male |
| Target number of participants | 88 |
| Total final enrolment | 109 |
| Key inclusion criteria | 1. Healthy males 2. Aged 19 to 45 years at screening 3. Able to understand and willing to follow the requirements for the study and provide written informed consent 4. Willing to avoid direct sunlight, use sun cream and cover arms and legs and to wear sunglasses and sunhat when outside during treatment and until final visit 5. Non-smokers from at least 3 months before receiving the first dose of study drug and for the duration of the study 6. Participants who are sexually active must agree to use barrier contraception with a spermicide from the time of the first dose until 3 months after the last dose (participants whose female partners are trying to become pregnant will be excluded) 7. Body mass index (BMI) ≥18 and ≤30 kg/m2 8. Body weight ≥55 kg at screening |
| Key exclusion criteria | 1. Current or recent (within 3 months of screening) use of sunbeds 2. Current or recent (less than 5 years) history of drug or alcohol abuse or a positive drugs of abuse test 3. Current or past history of psychiatric conditions or suicidal ideation 4. History or presence of any clinically relevant allergy 5. Consumption of prescription or over-the-counter medications (including vitamins, herbal and mineral supplements) within 14 days prior to study drug administration until (with the exception of occasional paracetamol) the end of the study |
| Date of first enrolment | 01/07/2018 |
| Date of final enrolment | 31/03/2020 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Richmond Pharmacology Ltd
1a Newcomen Street
London
SE1 1YR
United Kingdom
London
SE1 1YR
United Kingdom
Sponsor information
King's College London
University/education
University/education
16th Floor, Tower Wing, Guy's Hospital, Great Maze Pond
London
SE1 9RT
England
United Kingdom
| Website | Kcl.ac.uk |
|---|---|
"ROR" |
https://ror.org/0220mzb33 |
Funders
Funder type
Research council
Medical Research Council
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/12/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Trial data planned to be published at the end of the trial |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 15/07/2023 | 18/07/2023 | Yes | No |
Editorial Notes
18/07/2023: Publication reference and total final enrolment added.
28/04/2021: The following changes have been made:
1. The overall trial end date was changed from 31/03/2021 to 30/09/2021 and the plain English summary has been updated to reflect this change.
2. The intention to publish date was changed from 01/01/2021 to 01/12/2021.
18/05/2020: The following changes have been made:
1. The overall trial end date was changed from 01/06/2020 to 31/03/2021.
2. Surrey Clinical Research Centre was removed from the trial participating centres and Richmond Pharmacology Ltd added.
19/08/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/07/2019 to 31/03/2020.
2. The overall trial end date was changed from 01/08/2019 to 01/06/2020.
3. The intention to publish date was changed from 01/01/2020 to 01/01/2021.
4. IPD sharing statement added.
