Direct Information to At-risk Relatives (DIRECT)

Direct Letters to Relatives at Risk of Hereditary Cancer- a Multi-centre Randomised Controlled Trial of Healthcare-assisted Versus Family-mediated Risk Disclosure at Swedish Cancer Genetics Clinics (DIRECT-study)

This study evaluates if uptake of genetic counselling in high-risk families is increased when patients at cancer genetics clinics are being offered healthcare-assisted disclosure to at-risk relatives compared to current standard care (with family-mediated disclosure).

Patients/families who have undergone a cancer genetic investigation will be invited to participate in the study. All participants will receive standard care. Half of them will in addition be offered a healthcare-assisted disclosure with the service of direct letters to identified at-risk relatives distributed by the healthcare provider. After a year we will compare the proportion of at-risk relatives who have contacted a cancer genetic clinics in each study arm.

Study Overview

• Status: Active, not recruiting
• Conditions: Lynch Syndrome; Hereditary Breast and Ovarian Cancer Syndrome; Familial Breast Cancer; Hereditary Breast Cancer; Familial Colorectal Cancer
• Intervention / Treatment: Other: Standard care encouraging family-mediated disclosure of hereditary cancer risk; Other: Offer of health-care assisted disclosure by sending direct letters to at-risk relatives

Detailed Description

(When the formal study protocol is published, this section will instead refer to the published study protocol).

This study is a multi-centre open label, prospective, randomized controlled superiority trial comparing an intervention of healthcare-assisted disclosure with standard care of family-mediated disclosure of hereditary cancer risk information in high-risk families in Sweden.

SUBJECTS AND METHODS

Patients/families will be enrolled and allocated in parallel to intervention or standard care.

All participants receive standard genetic counseling and information summarizing the results of their family investigation. They are informed about preventive measures when applicable, and are encouraged to inform their at-risk relatives (t=0 months).

The intervention component is the addition of a healthcare-assisted disclosure procedure. Participants in the intervention arm will be offered the service of sending letters directly to their at-risk relatives.

If the participant approves the offer, letters will be sent to eligible at-risk relatives deemed to be recommended genetic counseling within a year.

The direct letter will inform the at-risk relative that a cancer genetic investigation has been conducted in the family and the implications for him or her, and their blood relatives.

To facilitate access to further information, contact details to the closest cancer genetics unit are included in the letter. The letters are sent with registered mail in neutral envelopes which means that recipients will have to show proof of identity to retrieve the letter from their local delivery service provider.

METHODS FOR ASSESSMENT OF STUDY OUTCOMES

For participants in both study arms, contact details of the at-risk relatives are identified in collaboration between health care provider and the participant. The health care provider records the name, approximate or exact year of birth and postal address of each at-risk relative for follow-up.

At the time of follow-up (t=12 months) the research nurse will check whether the relatives, listed one year before, have contacted a Swedish cancer genetic unit. Primary outcome data is retrieved from the patient data registries at each clinic. The research nurse will also record additional data points from CRFs, enabling analysis of the other pre-specified outcome measures in the intervention arm.

The outcome data are reported back to the national study secretariat as plain numbers without any personal details of the at-risk relatives.

SAMPLE SIZE AND STATISTICAL METHODS

For sample size calculation and statistical methods, see attached documents.

INTERNAL PILOT, AUDIT and PROGRESS CRITERIA

As this protocol has never been tested in Swedish clinical practice an internal pilot phase is included in the outline of the project.

Progress criteria at each study site are evaluated at internal pilot point and thereafter at formal audit at least yearly. Internal pilot point is set to the time when 20 individuals in total (across the 3 pilot study sites) have been included and treated according to protocol.

Continuation of the full-powered study at the specific study site will be determined by considering the criteria filled, the potentially necessary amendments, and the degree of which the amendments deviate from the original piloted study protocol.

The outcomes and process criteria are found in the attached document.

• Study Type: Interventional
• Enrollment (Estimated): 490
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Umeå, Sweden, 90185
    • Cancergenetisk mottagning

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. Patient being offered a cancer genetic investigation for hereditary breast, ovarian or colorectal cancer.
2. Written consent to participate the study,
3. Belonging to a family with; a) familial breast cancer, b) familial colorectal cancer, c) pathogenic variant in PALB2, BRCA1/2 (Hereditary breast cancer, hereditary breast and ovarian cancer), MLH1, MSH2, MSH6, PMS2 (Lynch syndrome) and
4. Having at least one eligible at-risk relative (family member deemed to be an ARR recommended genetic counseling within a year).

Exclusion Criteria:

1. Cannot convey personal opinions and preferences by themselves.
2. No eligible at-risk relatives living in Sweden.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control / Family-mediated disclosure (standard care); Genetic counseling according to current clinical practice	Other: Standard care encouraging family-mediated disclosure of hereditary cancer risk; At counseling, eligible at-risk relatives (who may benefit from disclosure of risk information) are listed on a specified protocol in collaboration between health care provider and the participant.
Experimental: Intervention / Health-care assisted disclosure; Genetic counseling according to current clinical practice with the addition of an offer from health care provider to mail letters directly to eligible at-risk relatives.	Other: Standard care encouraging family-mediated disclosure of hereditary cancer risk; At counseling, eligible at-risk relatives (who may benefit from disclosure of risk information) are listed on a specified protocol in collaboration between health care provider and the participant.; Other: Offer of health-care assisted disclosure by sending direct letters to at-risk relatives; The participant is offered that the health care provider at the cancer genetic unit mail a direct letter with personalized family risk information to all at-risk relatives that participant approve contact with.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Uptake of genetic counselling among the patient's at-risk relatives	Number of potential at-risk relatives who have contacted a Swedish cancer genetic unit out of the total number of potential at-risk relatives for each patient.	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intervention - Acceptance to offer (only intervention group)	Number of potential at-risk relatives that proband allowed contact with, compared to total number of potential at-risk relatives for that specific patient. [proportion]	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.
Intervention - Distribution of letters (only intervention group)	Number of at-risk relatives that proband allowed contact with and where contact data allowed distribution of direct letter, compared to total number of potential at-risk relatives for that specific patient. [proportion]	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.
Intervention - Collection of letters (only intervention group)	Number of at-risk relatives that proband allowed contact with, contact data was sufficient and the registered letter was collected from the post-office within 12 months, compared to total number of potential at-risk relatives for that specific patient. [proportion]	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.
Proportion of first-degree ARRs contacting a cancer genetics clinic	Comparing intervention and control group with respect to proportion of first-degree ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.
Proportion of distant ARRs contacting a cancer genetics clinic	Comparing intervention and control group with respect to proportion of second-degree, third-degree or more distant ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.	One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Collaborators and Investigators

• Sponsor: Umeå University
• Collaborators: Karolinska Institutet; Lund University; Göteborg University

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2020
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: December 6, 2019
• First Submitted That Met QC Criteria: December 12, 2019
• First Posted (Actual): December 13, 2019

Study Record Updates

• Last Update Posted (Actual): July 9, 2024
• Last Update Submitted That Met QC Criteria: July 7, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: prevention; genetic risk; hereditary cancer risk; family-mediated disclosure; healthcare-assisted disclosure; information disclosure; risk information
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Metabolic Diseases; Skin Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Disease; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Breast Diseases; Genetic Diseases, Inborn; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; DNA Repair-Deficiency Disorders; Ovarian Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Syndrome; Breast Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Hereditary Breast and Ovarian Cancer Syndrome
• Other Study ID Numbers: The Swedish DIRECT study; 2018-00964 (Other Grant/Funding Number: Swedish Research council for health, worklife and welfare); 2020-1107 (Other Grant/Funding Number: Swedish Cancer Society); 2022-02226 (Other Grant/Funding Number: Swedish research council); 86719 (Registry Identifier: RCC Cancerstudier i Sverige (in Swedish))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to aggregated data may be granted upon reasonable request to the principal investigator.
• IPD Sharing Time Frame: As requested by the publisher (peer reviewed journal).
• IPD Sharing Access Criteria: According to access to the peer reviewed journal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No