Clinical study

Clinical study of CDNF treatment for Parkinson’s disease

Study title: A Phase I-II, Randomised, Double-Blind, Placebo Controlled, Safety and Tolerability Study of Intermittent Bilateral Intraputamenal Cerebral Dopamine Neurotrophic Factor (CDNF) Infusions Administered via an Investigational Drug Delivery System to Patients with Idiopathic Parkinson’s Disease (PD) of Moderate Severity.

Treatment with CDNF (Cerebral Dopamine Neurotrophic Factor) aims to modify the progression of Parkinson’s disease and to provide symptomatic relief. However, as this is a first-in-human study, the primary objectives are safety and tolerability.

Study sponsor

Herantis Pharma Plc in collaboration with Renishaw Plc.

Study sites

Karolinska University Hospital, Department of Clinical Neuroscience, Stockholm, Sweden

Coordinating Investigator: Professor Per Svenningsson, specialist physician in neurology (Contact information)

Two other sites in Sweden and Finland plan to join the study at a later stage.

Regulatory and ethics approvals

The Swedish regulatory authority, MPA (Medical Products Agency), and the regional ethics committee in Stockholm have approved this study (Main study protocol covering the Surgery and Treatment period 1) to be conducted at the KarolinskaUniversity Hospital. The Treatment period 2 will be conducted under a separate Extension study protocol for which regulatory approval is pending.

The study is registered at the ClinicalTrials.gov database with a number NCT03295786 and at the European Clinical Trials Database (EudraCT) with a number 2015-004175-73.

Voluntary participation

Participation in the study is entirely voluntary. Anyone choosing to take part in the study can change their mind at any time and withdraw from the study without providing a reason. Non-participation or withdrawal from the study will not affect current or future care of patients. If a patient chooses to discontinue participation in the study, he or she will be asked to complete the end-of-study procedures (e.g. final medical examination and laboratory tests) for their own safety.

Participation in the study may also be stopped at any time by the responsible doctor on medical grounds.

The Informed Consent Form, containing all relevant patient information, will be made available in multiple languages. Currently, the following versions are available:

The study drug CDNF

The study drug is called CDNF (Cerebral Dopamine Neurotrophic Factor). It is a protein, which is found naturally in the body. In this study, its potential to prevent dopamine neuron degeneration and to stimulateneuron regeneration are being studied. As CDNF is a protein, it cannot be given as a pill or an injection as the body will not transport it to the brain. Therefore, in this study, CDNF will be given using a drug delivery system, which will be implanted into the brain by a neurosurgeon.

CDNF has not been studied previously in humans. In the initial study, CDNF will be compared to a placebo product in a 2:1 ratio. Patients will be randomly assigned to either placebo, CDNF mid-dose or CDNF high-dose groups, six patients in each group. After six months of treatment in the initial study (Treatment period 1), patients will be offered to participate in an extension study in which all patients will receive the active CDNF drug (Treatment period 2), pending approval by the regulatory authorities and local Ethics Committee.

Drug Delivery System

The CDNF drug is delivered to the brain via catheters, which are implanted by neurosurgeons in the putamen area of the brain. The catheters are connected to a port, which is fixed to the head, just behind the ear. The system also includes filters, which prevent bacteria and air from entering the brain.

This investigational drug delivery system has been previously implanted in more than forty patients in another clinical study.

Figure 1. Drug delivery device used in the study. (A) Location of different components after implantation surgery are shown. (B) Close-up view of the port structure. (C) Device in dosing mode, connected to the application set for drug dosing. List of components: 1 = transcutaneous skull-anchored port, 2 = subcutaneous lines connecting the port to the catheters, 3 = catheter entry sites (x4), the brain-dwelling parts of catheters are not shown, 4 = application set attached to the port [external infusion lines (not shown) will be connected to the application set for dosing].

Suitability of study patients

A total of eighteen patients will be enrolled in the study. Patients enrolling in the study will meet the following criteria:

  • Aged 35-75 years
  • Diagnosed with idiopathic Parkinson’s disease of moderate severity
  • Parkinson’s motor symptoms experienced for 5-15 years
  • Motor fluctuations experienced (“ON-OFF”). Ability to distinguish between different motor states, and to complete a symptom diary documenting these
  • Responsive to levodopa (minimum of 5 daily doses of levodopa)
  • No neurosurgical treatment for PD in the past, including deep brain stimulation (DBS)
  • No significant depression or other psychiatric disorders
  • No other medical conditions that can put the patient at risk to the study procedures, including bleeding disorders or chronic infections.

A patient’s eligibility to join the study will be assessed in more detail during the screening phase at the start of the study.

Those patients who do not meet the criteria for participation will be informed of the reasons, and they will continue to receive the same healthcare as they would normally receive.

How will the study be conducted?

  • CDNF will be compared to placebo. Two out of three patients will receive CDNF and one out of three will receive placebo during the Treatment period 1.
  • Six doses of either CDNF or placebo will be administered during the main study’s six-month period. (Treatment period 1).
  • All patients who participate in the extension study will receive six doses of CDNF over a further period of six months (Treatment period 2).
  • All patients assigned to receive CDNF will start on a low dose. An independent group of experts will review study data before the dose is increased in order to confirm that there are no safety concerns associated with the study drug.
  • For the main study, a patient’s participation will last for ten months and will include eighteen to nineteen visits:
    • Screening (2 visits)
    • Planning of surgery – Surgery: implantation of drug delivery system – Post-surgery follow-up (3 visits)
    • Test infusions with a contrast medium (gadolinium) to confirm the functionality of the drug delivery system (3 visits)
    • PET (positron emission tomography) examinations before the first and after the last dose (2 visits)
    • Baseline and randomisation to CDNF or placebo group (1 visit)
    • Dosing visits: CDNF or placebo (6-7 visits)
    • End-of-study visit (1 visit)
  • When participation in the main study is complete, patients may continue to the extension study, in which they will receive six CDNF doses over a further six months (Treatment period 2). Participating in the extension study will involve approximately ten more visits.

Study examinations and assessments

  • Physical examination: pulse rate, blood pressure, temperature, body weight and height.
  • ECG (electrocardiography) and blood and urine tests
  • HIV, hepatitis B and C blood tests (on first visit)
  • Pregnancy tests for women of childbearing age
  • Completion of a patient diary to record mobility and time asleep
  • Parkinson’s Kinetigraph (PKGTM) Data Logger: a watch-type device worn on the wrist for certain periods during the study to record movements
  • Questionnaires, rating scales and forms: quality of life, mood, memory, impulse control, mental health
  • Assessment of the port and the skin around the port. A photo will be taken of the port area.
  • Cerebrospinal fluid sampling by lumbar puncture
  • Magnetic resonance imaging (MRI)
  • Positron emission tomography scans (PET)
  • Computed tomography (CT)

On several visits, patients will be asked not to take their Parkinson’s medication for at least ten hours prior to your appointment. Patients can take their usual medication as soon as the assessments have been completed.

Patients will need to stay in the hospital or a hotel several times during the study, mostly one night but after the surgery for about four nights.

Figure 2. Study timeline and procedures per visit. The clinical study is composed of two studies performed under two different study protocols and patient consents. The first part of the study includes the device surgery and Treatment period 1. The second part includes Treatment period 2. At the end of Treatment period 2, the device will be closed from further access by removing the port. More information on study-related procedures can be obtained from the study centers.

Are there any restrictions during the study?

  • Swimming in a pool, diving and saunas are not recommended
  • Driving is not recommended until 24 hours after each dosing
  • Taking certain medicines or herbal remedies may not be permitted. Your normal Parkinson’s medication will continue uninterrupted throughout the study, with the exception of a temporary break just prior to certain hospital appointments
  • Patients are asked to eat a low-fat breakfast and lunch during certain visits

Are there alternatives to the study treatment?

The study doctor will discuss with patients other available treatments, including their benefits and risks. Participation in the study will not influence the usual treatment of Parkinson’s and patients will continue with their current medication. However, treatment with other investigational study drugs or investigational medical devices is not permitted during this study. There are also medications that may not used during this study. The study doctor will discuss these medicines in detail with all participating patients.

What are the possible risks or discomforts?

Implantation surgery:

  • General anaesthesia
  • Surgery can cause headache, necrosis, swelling, bleeding, infection of brain orscalp, and skin or skull around the port
  • Bleeding can cause serious symptoms such as seizure, paralysis, loss of concentration, memory loss, loss of power of speech, or loss of other brain function
  • Bruising in brain tissue, which can lead to stroke and/or paralysis
  • The catheters maybe inserted in the wrong position, resulting inadditionalsurgery to reposition them

Drug delivery system:

  • The port can cause local inflammation and skin reactions. The port can also loosen, in which case it has to be secured again
  • The body can react to the materials used in the drug delivery system
  • The catheters may get blocked

PET scan:

  • The helmet used in PET studies may feel uncomfortable

CDNF:

  • CDNF is an investigational drug and has not been given to humans before. Noside effects are known.

Gadolinium contrast agents (used in MRI):

  • Possible side effects related to gadolinium products used in planning of the surgery and test infusions: dizziness, headache, vomiting, nausea, changes in sense of taste, feeling hot or cold

Examinations and laboratory tests:

  • Drawing blood can be unpleasant and can cause pain, bruising, swelling or inflammation
  • The most common side effect of drawing off cerebrospinal fluid by lumbar puncture is a mild headache, which can last hours or days. In some cases, the headache can be more severe and dizziness, stiff neck or buzzing in the earsmay also occur.
  • Magnetic resonance imaging can be unpleasant if you suffer from claustrophobia
  • During computed tomography scan you will be exposed to small amount of radiation
  • Absence of normal Parkinson’s medication (during certain visits) may temporarily worsen your Parkinson’s symptoms. You can take your normal medication as soon as your examinations are completed, but it might take a few hours for symptoms to be well-controlled again.

What are the potential benefits?

The purpose of this study is to evaluate the safety and tolerability of CDNF and the implanted drug delivery system. A potential positive treatment effect on the symptoms of Parkinson’s disease will be evaluated, however, it is not known if you will have any benefit from the treatment. Data from this study may in the future benefit people with Parkinson’s.

After the study concludes

The study doctor will discuss the best care for patients in a timely manner before the end of the study. Patients will be informed about the options available for optimal treatment of their condition. The drug delivery device port behind the ear will be removed. The implanted drug delivery system will be left in place in the brain, unless otherwise decided by the study doctor.

What happens if relevant new information becomes available during the trial?

The study doctor and the sponsor are obliged to inform patients if any new information emerges during the study which could affect patients’ decision to take part or continue. The study doctor will discuss such information with the patients, and may possibly decide that it is best for a patient to withdraw from this study.

How is personal data handled?

All study data are confidential and will be processed using only a code number. The study doctor will keep a code list in which the patients’ code numbers are linked to personal details, such as name and date of birth.

The study results may be published in medical journals and presented in scientific conferences, meetings and seminars. However, the identity of patients will not be revealed in any such report or presentation. For specific purposes, information may be transferred to regulatory authorities and to organizations cooperating with the study sponsor.

A description of the study is available in the ClinicalTrials.gov database (NCT03295786). This website will not have information that could identify you as a study participant but will include a brief summary of the study results. This site shows information only in English, but patients can contact the study staff at any time to ask about the publicly available information in patients’ own language.

If a patient decides to leave the study prematurely, the data that has been collected before the withdrawal of the consent will be used in the evaluation of the study.

Patients have the right to obtain once a year, free of charge, details of what personal information has been recorded about the patient, from where the information has been obtained and how it has been disclosed. Patients also have the right to request that any incorrect information be corrected. All patients are encouraged talk to the study doctor if any erroneous information is noticed.

In order to confirm that the study has been duly conducted and to confirm the data collected about patients is correct, certain authorised people may have access to the medical records of the patients of the study. An authorised representative of the regulatory authority or the ethics committee may require access to the patients medical records in order to verify that the study has been duly carried out.

Insurance

As in routine national healthcare, patients participating in this study are covered by the national patient insurance. The study sponsor has taken an insurance to cover the expenses of any damages that are considered to result from the patients’ participation in the study. Patients should contact their study doctor if they believe they have suffered an injury as a result of their participation in this study.

Financial compensation

The hospital has received funding from the European Commission to perform this study. All patients’ participation costs will be covered, including travel to appointments and possible losses of income for the time spent at the study visits.