FRAGMATIC

A randomised phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy In patients with lung Cancer.

FRAGMATIC was a multicentre Phase III randomised controlled trial. It was the largest UK trial of lung cancer patients with low molecular weight heparin.

This trial wanted to see if:

• the blood thinning drug dalteparin (Fragmin) could reduce the number of blood clots people had during treatment for lung cancer;
• dalteparin could help stop cancer cells spreading through the bloodstream to other parts of the body.

Surgery, chemotherapy or radiotherapy can all be used to treat lung cancer. Patients may have more than one of these treatments. Blood clots are quite common in people who have lung cancer and cancer treatment can increase the risk of blood clots. Dalteparin is a blood thinning drug (anticoagulant) that is widely used to prevent and treat blood clots. Doctors thought that dalteparin might also affect how cancer cells spread through the bloodstream, but they didn’t know this for sure.

The aims of this trial were:

• to see if having dalteparin as well as standard treatment was better than having standard treatment alone for lung cancer;
• to see if people having dalteparin injections had fewer blood clots than people who didn’t have the injections;
• to learn more about the side effects of having regular dalteparin injections at the same time as standard treatment for lung cancer;
• to learn more about the experiences of the trial participants through qualitative interviews and Interpretive Phenomenological Analysis (IPA);
• to learn more about the cost effectiveness and cost utility of having dalteparin as well as standard treatment alone for lung cancer.

Full details of the trial protocol can be found in the following published article:

FRAGMATIC: a randomised phase III clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer. Griffiths GO1, Burns S, Noble SI, Macbeth FR, Cohen D, Maughan TSBMC Cancer. 2009 Oct 6;9:355. doi: 10.1186/1471-2407-9-355.

FRAGMATIC participants were also asked to consider participating in the T-FRAG trial which collected cancer tissue biopsy and blood samples to gain a better understanding of dalteparin in the treatment of lung cancer.

Results

2,202 people took part in this trial. Half had standard treatment. The other half had dalterparin with standard treatment. The dalteparin was given as an injection in the stomach, thigh or buttock once every day for a maximum of 24 weeks.

The trial team followed people up after their treatment. After just under 2 years they looked at the average length of time people lived. For both groups it was about 10 months. They also looked at the average length of time it took for the cancer to spread. For both groups it was about 9 weeks.

The number of people who developed blood clots was:

• 61 of those who had dalteparin;
• 107 of those who didn’t have dalteparin.

The side effects were similar for both groups except that those who had dalteparin reported having:

• more diarrhoea;
• more episodes of bleeding.

The trial team concluded that although having dalteparin reduces the number of blood clots, having it also increased the risk of bleeding, and so it should not be given to everyone with lung cancer. There was also no increase in people living longer. They say that future research should concentrate on looking at giving blood thinning drugs to specific groups of people with lung cancer who have been identified as having a higher risk of developing a blood clot.

The trial data was further analysed to see if there was a significant survival benefit for any of the following subgroups of patients: sex, age, BMI, histological subtype or advanced stage. The results showed that it is unlikely that heparin thromboprophylaxis in a broad population of patients with either small cell lung cancer or non-small cell lung cancer provides a clinically significant improvement in overall survival.

Ten participants from the control and intervention arms of FRAGMATIC also took part in a qualitative sub-study. They were interviewed at up to three time points during their time in the trial to find out their motivational reasons for joining the trial and their level of understanding of the trial. Their interviews were analysed using Interpretive Phenomenological Analysis (IPA). The researchers concluded that there were potential harms and benefits of participation in non-placebo controlled trials of patients with advanced lung cancer, and that these harms and benefits should be considered in future research, and when caring for, patients with advanced cancer.

The data collected in this study is being used currently:

• to learn more about the cost effectiveness and cost utility of having dalteparin as well as standard treatment alone for lung cancer;
• to see if the Kohrana Risk Score for Venous Thromboembolism in Cancer Patients works in this population of patients;
• to compare current practice of first line treatment for lung cancer to NICE guidelines.

Further details of the trial results can be found in the following published articles:

1. Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial.  Macbeth F, Noble S, Evans J, Ahmed S, Cohen D, Hood K, Knoyle D, Linnane S, Longo M, Moore B, Woll PJ, Appel W, Dickson J, Ferry D, Brammer C, Griffiths G. J Clin Oncol. 2016 Feb 10;34(5):488-94. doi: 10.1200/JCO.2015.64.0268. Epub 2015 Dec 23.
2. "I didn't really understand it, I just thought it'd help": exploring the motivations, understandings and experiences of patients with advanced lung cancer participating in a non-placebo clinical IMP trial. Harrop E, Noble S, Edwards M, Sivell S, Moore B, Nelson A; FRAGMATIC Trial Management Group (TMG). Trials. 2016 Jul 20;17(1):329. doi: 10.1186/s13063-016-1460-8.
3. Macbeth F, Carter B, Noble S, Hood K. Transl Lung Cancer Res. 2016 Jun;5(3):347-9. doi: 10.21037/tlcr.2016.05.07.Further results of the FRAGMATIC trial of thromboprophylaxis in lung cancer.